Immunomodulator compounds

ABSTRACT

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2a, R2b, R2c, R3, R4, R5, R6a, R6b, m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/633,569 filed Jun. 26, 2017, which is an application claiming benefitof priority under 35 U.S.C. § 119(e) to U.S. Provisional PatentApplication Ser. No. 62/440,100 filed on Dec. 29, 2016 and to U.S.Provisional Patent Application Ser. No. 62/355,119 filed on Jun. 27,2016, the contents of each are incorporated herein by reference in theirentirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not applicable

BACKGROUND OF THE DISCLOSURE

Programmed cell death-1 (PD-1) is a member of the CD28 superfamily thatdelivers negative signals upon interaction with its two ligands, PD-L1or PD-L2. PD-1 and its ligands are broadly expressed and exert a widerange of immunoregulatory roles in T cells activation and tolerance.PD-1 and its ligands are involved in attenuating infectious immunity andtumor immunity, and facilitating chronic infection and tumorprogression.

Modulation of the PD-1 pathway has therapeutic potential in varioushuman diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011);350:17-37). Blockade of the PD-1 pathway has become an attractive targetin cancer therapy. Therapeutic antibodies that block the programmed celldeath protein-1 (PD-1) immune checkpoint pathway prevent T-cell downregulation and promote immune responses against cancer. Several PD-1pathway inhibitors have shown robust activity in various phases ofclinical trials (R D Harvey, Clinical Pharmacology and Therapeutics(2014); 96(2), 214-223).

Accordingly, agents that block the interaction of PD-L1 with either PD-1or CD80 are desired. Some antibodies have been developed andcommercialized. However there is still a need for alternative compoundssuch as small molecules which may have advantageous characteristics interm of oral administration, stability, bioavailability, therapeuticindex, and toxicity. A few patent applications disclosing non-peptidicsmall molecules have been published (WO 2015/160641, WO 2015/034820, andWO 2017/066227 from BMS; WO 2015/033299 and WO 2015/033301 fromAurigene; WO 2017/070089, US 2017/0145025 and WO 2017/106634 fromIncyte) However, there remains a need for alternative small moleculesuseful as inhibitors of the PD-1 pathway.

BRIEF SUMMARY OF THE DISCLOSURE

In one aspect, provided herein are compounds having the formula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(2a),R^(2b), R^(2c), R³, R⁴, R⁵, R^(6a), R^(6b), m and n are as definedherein.

In addition to the compounds provided herein, the present disclosurefurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods associated with preparation and useof such compounds. In some embodiments, the compounds are used intherapeutic methods to treat diseases associated with the PD-1/PD-L1pathway.

BRIEF DESCRIPTION OF THE DRAWINGS

Not applicable

DETAILED DESCRIPTION OF THE DISCLOSURE Abbreviation and Definitions

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

The terms “about” and “approximately” shall generally mean an acceptabledegree of error for the quantity measured given the nature or precisionof the measurements. Typical, exemplary degrees of error are within 20percent (%), preferably within 10%, and more preferably within 5% of agiven value or range of values. Alternatively, and particularly inbiological systems, the terms “about” and “approximately” may meanvalues that are within an order of magnitude, preferably within 5-foldand more preferably within 2-fold of a given value. Numerical quantitiesgiven herein are approximate unless stated otherwise, meaning that theterm “about” or “approximately” can be inferred when not expresslystated.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkyl” in itsbroadest sense is also meant to include those unsaturated groups such asalkenyl and alkynyl groups. The term “alkenyl” refers to an unsaturatedalkyl group having one or more double bonds. Similarly, the term“alkynyl” refers to an unsaturated alkyl group having one or more triplebonds. Examples of such unsaturated alkyl groups include vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. The term “cycloalkyl” refers to hydrocarbonrings having the indicated number of ring atoms (e.g., C₃₋₆cycloalkyl)and being fully saturated or having no more than one double bond betweenring vertices. “Cycloalkyl” is also meant to refer to bicyclic andpolycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclic orpolycyclic rings may be fused, bridged, spiro or a combination thereof.The term “heterocycloalkyl” or “heterocyclyl” refers to a cycloalkylgroup that contain from one to five heteroatoms selected from N, O, andS, wherein the nitrogen and sulfur atoms are optionally oxidized, andthe nitrogen atom(s) are optionally quaternized. The heterocycloalkylmay be a monocyclic, a bicyclic or a polycylic ring system. The bicyclicor polycyclic rings may be fused, bridged, spiro or a combinationthereof. It is understood that the recitation for C₄₋₁₂ heterocyclyl,refers to a heterocycloalkyl moiety having from 5 to 12 ring memberswhere at least one of the ring members is a heteroatom. Non limitingexamples of heterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present disclosure. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “hydroxyalkyl” or “alkyl-OH” refers to an alkyl group, asdefined above, where at least one of the hydrogen atoms is replaced witha hydroxy group. As for the alkyl group, hydroxyalkyl groups can haveany suitable number of carbon atoms, such as C₁₋₆. Exemplaryalkylhydroxy groups include, but are not limited to, hydroxy-methyl,hydroxyethyl (where the hydroxy is in the 1- or 2-position),hydroxypropyl (where the hydroxy is in the 1-, 2- or 3-position), etc.

The term “C₁₋₃ alkyl-guanidinyl” refers to a C₁₋₃ alkyl group, asdefined above, where at least one of the hydrogen atoms is replaced witha guanidinyl group (—NC(NH)NH₂). In some embodiments, C₁₋₃alkyl-guanidinyl refers a C₁₋₃ alkyl group where one of the hydrogenatoms is replaced with a guanidinyl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. It is understoodthat the recitation for C₅₋₁₀ heteroaryl, refers to a heteroaryl moietyhaving from 5 to 10 ring members where at least one of the ring membersis a heteroatom. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl, while non-limiting examples of heteroaryl groupsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl,quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl,benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for eachof the above noted aryl and heteroaryl ring systems are selected fromthe group of acceptable substituents described below.

The term “carbocyclic ring” or “carbocyclyl” refers to cyclic moietieswith only carbon atoms as ring vertices. Carbocyclic ring moieties aresaturated or unsaturated and can be aromatic. Generally, carbocyclicmoieties have from 3 to 10 ring members. Carbocylic moieties withmultiple ring structure (e.g. bicyclic) can include a cycloalkyl ringfused to a aromatic ring (e.g. 1,2,3,4-tetrahydronaphthalene). Thus,carboclicic rings include cyclopentyl, cyclohexenyl, naphthyl, and1,2,3,4-tetrahydronaphthyl. The term “heterocyclic ring” refers to both“heterocycloalkyl” and “heteroaryl” moieties. Thus, heterocyclic ringsare saturated or unsaturated and can be aromatic. Generally,heterocyclic rings are 4 to 10 ring members and include piperidiyl,tetrazinyl, pyrazolo, and indolyl.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like).

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below. For brevity, the terms aryl and heteroaryl willrefer to substituted or unsubstituted versions as provided below, whilethe term “alkyl” and related aliphatic radicals is meant to refer tounsubstituted version, unless indicated to be substituted.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be avariety of groups selected from: -halogen, —OR′, —NR′R″, —SR′,—SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R″, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R″′ eachindependently refer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstitutedheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted C₁₋₈ alkyl, C₁₋₈ alkoxy or C₁₋₈ thioalkoxy groups, orunsubstituted aryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant toinclude 1-pyrrolidinyl and 4-morpholinyl. The term “acyl” as used byitself or as part of another group refers to an alkyl radical whereintwo substitutents on the carbon that is closest to the point ofattachment for the radical is replaced with the substitutent ═O (e.g.,—C(O)CH₃, —C(O)CH₂CH₂OR′ and the like).

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R″, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R″′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R″′ are independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, andunsubstituted aryloxy-C₁₋₄ alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “ionic liquid” refers to any liquid that contains mostly ions.Preferably, in the present disclosure, “ionic liquid” refers to thesalts whose melting point is relatively low (e.g., below 250° C.).Examples of ionic liquids include but are not limited to1-butyl-3-methylimidazolium tetrafluoroborate,1-hexyl-3-methylimidazolium tetrafluoroborate,1-octyl-3-methylimidazolium tetrafluoroborate,1-nonyl-3-methylimidazolium tetrafluoroborate,1-decyl-3-methylimidazolium tetrafluoroborate,1-hexyl-3-methylimidazolium hexafluorophosphate and1-hexyl-3-methylimidazolium bromide, and the like.

The terms “patient” and “subject” include primates (especially humans),domesticated companion animals (such as dogs, cats, horses, and thelike) and livestock (such as cattle, pigs, sheep, and the like).

As used herein, the term “treating” or “treatment” encompasses bothdisease-modifying treatment and symptomatic treatment, either of whichmay be prophylactic (i.e., before the onset of symptoms, in order toprevent, delay or reduce the severity of symptoms) or therapeutic (i.e.,after the onset of symptoms, in order to reduce the severity and/orduration of symptoms).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occuring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentdisclosure contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent disclosure. The compounds of the present disclosure may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.For example, the compounds may be prepared such that any number ofhydrogen atoms are replaced with a deuterium (²H) isotope. The compoundsof the present disclosure may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. Unnatural proportions of an isotope may be defined as rangingfrom the amount found in nature to an amount consisting of 100% of theatom in question. For example, the compounds may incorporate radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) orcarbon-13 (¹³C). Such isotopic variations can provide additionalutilities to those described elsewhere within this application. Forinstance, isotopic variants of the compounds of the disclosure may findadditional utility, including but not limited to, as diagnostic and/orimaging reagents, or as cytotoxic/radiotoxic therapeutic agents.Additionally, isotopic variants of the compounds of the disclosure canhave altered pharmacokinetic and pharmacodynamic characteristics whichcan contribute to enhanced safety, tolerability or efficacy duringtreatment. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are intended to be encompassedwithin the scope of the present disclosure.

Compounds

In one aspect, the present disclosure provides compounds having theformula (II)

or a pharmaceutically acceptable salt thereof; wherein:

-   R¹ is selected from the group consisting of halogen, C₅₋₈    cycloalkyl, C₆₋₁₀ aryl and thienyl, wherein the C₆₋₁₀ aryl and    thienyl are optionally substituted with 1 to 5 R^(x) substituents;-   each R^(x) is independently selected from the group consisting of    halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),    —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(a),    —NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),    —O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X—NR^(a)R^(b),    —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b),    wherein each X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is    independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈    haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, wherein the five or six-membered ring is optionally    substituted with oxo; each R^(c) is independently selected from the    group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl and C₁₋₈    haloalkyl; and optionally when two R^(x) substituents are on    adjacent atoms, they are combined to form a fused five, six or    seven-membered carbocyclic or heterocyclic ring optionally    substituted with from 1 to 3 substituents independently selected    from halo, oxo, C₁₋₈ haloalkyl and C₁₋₈ alkyl;-   each R^(2a), R^(2b) and R^(2c) is independently selected from the    group consisting of H, halogen, —CN, —R^(d), —CO₂R^(e),    —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e),    —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e),    —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),    —O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),    —X²—CONR^(e)R^(f), —SF₅, —S(O)₂NR^(e)R^(f), C₆₋₁₀ aryl and C₅₋₁₀    heteroaryl, wherein each X² is a C₁₋₄ alkylene; each R^(e) and R^(f)    is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈    haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O and S, and optionally substituted with oxo; each R^(d) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl;-   R³ is selected from the group consisting of —NR^(g)R^(h) and C₄₋₁₂    heterocyclyl, wherein the C₄₋₁₂ heterocyclyl is optionally    substituted with 1 to 6 R^(y);-   each R^(y) is independently selected from the group consisting of    halogen, —CN, —R^(i), —CO₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₆ alkyl-OH,    —C(O)R^(j), —OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k),    CONOH, PO₃H₂, —NR^(j)—C₁₋₆ alkyl-C(O)₂R^(k), —NR^(j)C(O)NR^(j)R^(k),    —NR^(j)R^(k), —OR^(j), —S(O)₂NR^(j)R^(k), —O—C₁₋₆alkyl-OR^(j),    —O—C₁₋₆ alkyl-NR^(j)R^(k), —O—C₁₋₆ alkyl-CO₂R^(j), —O—C₁₋₆    alkyl-CONR^(j)R^(k), —C₁₋₆ alkyl-OR^(j), —C₁₋₆ alkyl-NR^(j)R^(k),    —C₁₋₆ alkyl-CO₂R^(j), —C₁₋₆ alkyl-CONR^(j)R^(k), and SF₅,    -   wherein the C₁₋₆ alkyl portion of R^(y) is optionally further        substituted with OH, S₂NH₂, CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl        or CO₂H, wherein each R^(j) and R^(k) is independently selected        from hydrogen, C₁₋₈ alkyl optionally substituted with 1 to 2        substituents selected from OH, SO₂NH₂, CONH₂, CONOH, PO₃H₂,        COO—C₁₋₈alkyl or CO₂H, and C₁₋₈ haloalkyl optionally substituted        with 1 to 2 substituents selected from OH, S₂NH₂, CONH₂, CONOH,        PO₃H₂, COO—C₁₋₈alkyl or CO₂H, or when attached to the same        nitrogen atom R^(j) and R^(k) can be combined with the nitrogen        atom to form a five or six-membered ring having from 0 to 2        additional heteroatoms as ring members selected from N, O or S,        and optionally substituted with oxo; each R^(i) is independently        selected from the group consisting of —OH, C₁₋₈ alkyl, C₂₋₈        alkenyl, and C₁₋₈ haloalkyl each of which may be optionally        substituted with OH, SO₂NH₂, CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl        or CO₂H;-   R^(g) is selected from the group consisting of H, C₁₋₈ haloalkyl and    C₁₋₈ alkyl;-   R^(h) is selected from —C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH,    C₁₋₈ alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈    alkyl-PO₃H₂, C₁₋₈ alkyl-CONOH, C₁₋₈ alkyl-NR^(h1)R^(h2),    —C(O)—C₁₋₈alkyl, —C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀    cycloalkyl, —C₃₋₁₀ cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, C₄₋₈    heterocyclyl, —C₄₋₈ heterocyclyl-COOH, —C₄₋₈ heterocyclyl-OH, —C₁₋₈    alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₅₋₁₀    heteroaryl, —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, C₁₀ carbocyclyl, —C₁₋₈    alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —C₁₋₈    alkyl-NH(C═O)—C₁₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈    alkyl-NH(C═O)—C₁₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-COOH,    and —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OH optionally substituted with    CO₂H; or    -   R^(h) combined with the N to which it is attached is a mono-,        di- or tri-peptide comprising 1-3 natural amino acids and 0-2        non-natural amino acids, wherein    -   the non-natural aminoacids have an alpha carbon substituent        selected from the group consisting of C₂₋₄ hydroxyalkyl, C₁₋₃        alkyl-guanidinyl, and C₁₋₄ alkyl-heteroaryl,    -   the alpha carbon of each natural or non-natural amino acids are        optionally further substituted with a methyl group, and    -   the terminal moiety of the mono-, di-, or tri-peptide is        selected from the group consisting of C(O)OH, C(O)O—C₁₋₆ alkyl,        and PO₃H₂, wherein    -   R^(h1) and R^(h2) are each independently selected from the group        consisting of H, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl;    -   the C₁₋₈ alkyl portions of R^(h) are optionally further        substituted with from 1 to 3 substituents independently selected        from OH, COOH, SO₂NH₂, CONH₂, CONOH, COO—C₁₋₈ alkyl, PO₃H₂ and        C₅₋₆ heteroaryl optionally substituted with 1 to 2 C₁₋₃ alkyl        substituents,    -   the C₁₀ carbocyclyl, C₅₋₁₀ heteroaryl and the C₆₋₁₀ aryl        portions of R^(h) are optionally substituted with 1 to 3        substituents independently selected from OH, B(OH)₂, COOH,        SO₂NH₂, CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl, C₁₋₄alkyl,        C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkyl CONH₂,        C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, C₁₋₄alkyl-COOH, and phenyl and    -   the C₄₋₈ heterocyclyl and C₃₋₁₀ cycloalkyl portions of R^(h) are        optionally substituted with 1 to 4 R^(w) substituents;-   each R^(w) substituent is independently selected from C₁₋₄ alkyl,    C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄ alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂,    C₁₋₄ alkyl-CONOH, C₁₋₄ alkyl-PO₃H, OH, COO—C₁₋₈ alkyl, COOH, SO₂NH₂,    CONH₂, CONOH, PO₃H₂ and oxo;-   R⁴ is selected from the group consisting of O—C₁₋₈ alkyl, O—C₁₋₈    haloalkyl, O—C₁₋₈ alkyl-R^(z), C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, —O—C₁₋₄    alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl, wherein the    C₆₋₁₀ aryl and the C₅₋₁₀ heteroaryl are optionally substituted with    1 to 5 R^(z);-   each R^(z) is independently selected from the group consisting of    halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),    —O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),    —X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅,    —S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), and three to seven-membered    carbocyclic or four to seven-membered heterocyclic ring wherein the    three to seven-membered carbocyclic or four to seven-membered    heterocyclic ring is optionally substituted with 1 to 5 R^(t),    wherein each R^(t) is independently selected from the group    consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, —CO₂R^(n), —CONR^(n)R^(p),    —C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),    —O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),    —X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅, and    —S(O)₂NR^(n)R^(p);-   wherein each X³ is a C₁₋₄ alkylene; each R^(n) and R^(p) is    independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈    haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(m) is    independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl; and optionally when two R^(z)    substituents are on adjacent atoms, they are combined to form a    fused five or six-membered carbocyclic or heterocyclic ring    optionally substituted with oxo;-   n is 0, 1, 2 or 3;-   each R⁵ is independently selected from the group consisting of    halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),    —OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),    —NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),    —O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),    —X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅,    —S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r)    and R^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(q) is    independently selected from the group consisting of C₁₋₈ alkyl, and    C₁₋₈ haloalkyl;-   R^(6a) is selected from the group consisting of H, C₁₋₄ alkyl and    C₁₋₄ haloalkyl;-   each R^(6b) is independently selected from the group consisting of    F, C₁₋₄ alkyl, O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each    R^(u) and R^(v) is independently selected from hydrogen, C₁₋₈ alkyl,    and C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can    be combined with the nitrogen atom to form a five or six-membered    ring having from 0 to 2 additional heteroatoms as ring members    selected from N, O or S, and optionally substituted with oxo; and-   m is 0, 1, 2, 3 or 4

In some embodiments, the present disclosure provides compounds havingthe formula (II)

or a pharmaceutically acceptable salt thereof; wherein:

-   R¹ is selected from the group consisting of C₆₋₁₀ aryl and thienyl,    wherein the C₆₋₁₀ aryl and thienyl are optionally substituted with 1    to 5 R^(x) substituents;-   each R^(x) is independently selected from the group consisting of    halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),    —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),    —NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),    —O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X¹—NR^(a)R^(b),    —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, —S(O)₂NR^(a)R^(b), wherein    each X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is independently    selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when    attached to the same nitrogen atom can be combined with the nitrogen    atom to form a five or six-membered ring having from 0 to 2    additional heteroatoms as ring members selected from N, O or S,    wherein the five or six-membered ring is optionally substituted with    oxo; each R^(c) is independently selected from the group consisting    of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl and C₁₋₈ haloalkyl; and    optionally when two R^(x) substituents are on adjacent atoms, they    are combined to form a fused five, six or seven-membered carbocyclic    or heterocyclic ring optionally substituted with from 1 to 3    substituents independently selected from oxo, C₁₋₈ haloalkyl and    C₁₋₈ alkyl;-   each R^(2a), R^(2b) and R^(2c) is independently selected from the    group consisting of H, halogen, —CN, —R^(d), —CO₂R^(e),    —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e),    —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e),    —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),    —O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),    —X²—CONR^(e)R^(f), —SF₅, —S(O)₂NR^(e)R^(f), wherein each X² is a    C₁₋₄ alkylene; each R^(e) and R^(f) is independently selected from    hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the    same nitrogen atom can be combined with the nitrogen atom to form a    five or six-membered ring having from 0 to 2 additional heteroatoms    as ring members selected from N, O or S, and optionally substituted    with oxo; each R^(d) is independently selected from the group    consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl;-   R³ is selected from the group consisting of NR^(g)R^(h) and C₄₋₁₂    heterocyclyl wherein the C₄₋₁₂ heterocyclyl is optionally    substituted with 1 to 6 R^(y);-   each R^(y) is independently selected from the group consisting of    halogen, —CN, —R^(i), —C₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₆ alkyl-OH,    —C(O)R^(j), —OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k),    —CONOH, —PO₃H₂, —NR^(j)—C₁₋₆ alkyl-C(O)₂R^(k),    —NR^(j)C(O)NR^(j)R^(k), —NR^(j)R^(k), —OR^(j), —S(O)₂NR^(j)R^(k),    —O—C₁₋₆alkyl-OR^(j), —O—C₁₋₆ alkyl-NR^(j)R^(k), —O—C₁₋₆    alkyl-CO₂R^(j), —O—C₁₋₆ alkyl-CONR^(j)R^(k), —C₁₋₆ alkyl-OR^(j),    —C₁₋₆ alkyl-NR^(j)R^(k), —C₁₋₆ alkyl-CO₂R^(j), —C₁₋₆    alkyl-CONR^(j)R^(k), and SF₅, wherein the C₁₋₆ alkyl is optionally    substituted with OH, SO₂NH₂, CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl or    CO₂H, wherein each R^(j) and R^(k) is independently selected from    hydrogen, C₁₋₈ alkyl optionally substituted with OH, SO₂NH₂, CONH₂,    CONOH, PO₃H₂, COO—C₁₋₈alkyl or CO₂H, and C₁₋₈ haloalkyl optionally    substituted with OH, SO₂NH₂, CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl or    CO₂H, or when attached to the same nitrogen atom R^(j) and R^(k) can    be combined with the nitrogen atom to form a five or six-membered    ring having from 0 to 2 additional heteroatoms as ring members    selected from N, O or S, and optionally substituted with oxo; each    R^(i) is independently selected from the group consisting of C₁₋₈    alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl each of which may be    optionally substituted with OH, SO₂NH₂, CONH₂, CONOH, PO₃H₂,    COO—C₁₋₈alkyl or CO₂H;-   R^(g) is selected from the group consisting of H, C₁₋₈ haloalkyl and    C₁₋₈ alkyl;-   R^(h) is selected from —C₁₋₈ alkyl, —C₁₋₈ alkyl-N(C═O)—C₁₋₈ alkenyl,    —C₁₋₈alkyl-N(C═O)—C₁₋₈alkyl, —C₁₋₈alkyl-N(C═O)—C₁₋₈ alkynyl,    —C₁₋₈alkyl-(C═O)—N—C₁₋₈ alkyl-OH optionally substituted with CO₂H,    —C₁₋₈ alkyl-(C═O)—N—C₁₋₈ alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀    cycloalkyl-COOH, C₄₋₈ heterocyclyl, —C₄₋₈ heterocyclyl-COOH,    —C₄₋₈heterocyclyl-OH, —C₃₋₁₀ cycloalkyl-OH, —C(O)—C₁₋₈alkyl,    —C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₁₋₈ haloalkyl, —C₁₋₈    alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl,    —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, —C₁₋₈ alkyl-C₆₋₁₀ aryl, C₁₋₈ alkyl-OH,    C₁₋₈ alkyl-CONH₂, C₁₋₈alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂, C₁₋₈    alkyl-CONOH, C₃₋₁₀ cycloalkyl, and C₁₋₈ alkyl-COOH, wherein the    C₁₋₈alkyl is optionally substituted with from 1 to 3 substituents    independently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH,    COO—C₁₋₈alkyl and PO₃H₂, wherein the C₅₋₁₀ heteroaryl and the C₆₋₁₀    aryl are optionally substituted with 1 to 3 substituents    independently selected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, CONOH,    PO₃H₂, COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂,    C₁₋₄alkyl CONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, and    C₁₋₄alkyl-COOH, and wherein the C₄₋₈ heterocyclyl and C₃₋₁₀    cycloalkyl are optionally substituted with 1 to 3 R^(w)    substituents;-   each R^(w) substituent is independently selected from C₁₋₄ alkyl,    C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄ alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂,    C₁₋₄ alkyl-CONOH, C₁₋₄ alkyl-PO₃H, OH, COO—C₁₋₈alkyl, COOH, SO₂NH₂,    CONH₂, CONOH, PO₃H₂ and oxo;-   R⁴ is selected from the group consisting of O—C₁₋₈ alkyl, O—C₁₋₈    haloalkyl, O—C₁₋₈ alkyl-R^(z), C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, —O—C₁₋₄    alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl, wherein the    C₆₋₁₀ aryl and the C₅₋₁₀ heteroaryl are optionally substituted with    1 to 5 R^(z);-   each R^(z) is independently selected from the group consisting of    halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),    —O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),    —X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅,    —S(O)₂NR^(n)R^(p), and three to seven-membered carbocyclic or four    to seven-membered heterocyclic ring wherein the three to    seven-membered carbocyclic or four to seven-membered heterocyclic    ring is optionally substituted with 1 to 5 R^(t), wherein each R^(t)    is independently selected from the group consisting of C₁₋₈alkyl,    C₁₋₈haloalkyl, —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),    —O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),    —X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅, and    —S(O)₂NR^(n)R^(p);    -   wherein each X³ is a C₁₋₄ alkylene; each R^(n) and R^(p) is        independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈        haloalkyl, or when attached to the same nitrogen atom can be        combined with the nitrogen atom to form a five or six-membered        ring having from 0 to 2 additional heteroatoms as ring members        selected from N, O or S, and optionally substituted with oxo;        each R^(m) is independently selected from the group consisting        of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; and optionally        when two R^(z) substituents are on adjacent atoms, they are        combined to form a fused five or six-membered carbocyclic or        heterocyclic ring optionally substituted with oxo;-   the subscript n is 0, 1, 2 or 3;-   each R⁵ is independently selected from the group consisting of    halogen, —CN, —R^(q), —C₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),    —OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),    —NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),    —O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),    —X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅,    —S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r)    and R^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(q) is    independently selected from the group consisting of C₁₋₈ alkyl, and    C₁₋₈ haloalkyl;-   R^(6a) is selected from the group consisting of H, C₁₋₄ alkyl and    C₁₋₄ haloalkyl;-   each R^(6b) is independently selected from the group consisting of    F, C₁₋₄ alkyl, O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each    R^(u) and R^(v) is independently selected from hydrogen, C₁₋₈ alkyl,    and C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can    be combined with the nitrogen atom to form a five or six-membered    ring having from 0 to 2 additional heteroatoms as ring members    selected from N, O or S, and optionally substituted with oxo; and-   the subscript m is 0, 1, 2, 3 or 4.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof has the formula (IIa)

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof having the formula (IIb)

In some embodiments, R¹ is selected from the group consisting of phenyland thienyl, wherein the phenyl and thienyl are optionally substitutedwith 1 to 5 R^(x) substituents. In some embodiments, R¹ is phenyloptionally substituted with 1 or 2 R^(x) wherein each R^(x) isindependently selected from halogen, C₁₋₈ alkyl, O—C₁₋₈ alkyl, O—C₁₋₈haloalkyl, —NR^(a)R^(b), and CN, and optionally when two R^(x)substituents are on adjacent atoms, they are combined to form a fusedsix-membered heterocyclic ring optionally substituted with from 1 to 3substituents independently selected from oxo, C₁₋₈ haloalkyl and C₁₋₈alkyl. In some embodiments, R¹ is phenyl optionally substituted with F.In some embodiments, R¹ is selected from the group consisting of:

In some embodiments, each R^(2a), R^(2b) and R^(2c) is independentlyselected from the group consisting of H, halogen, —CN, —R^(d),—NR^(e)R^(f), —OR^(e), —X²—OR^(e), —X²—NR^(e)R^(f), wherein X² is C₁₋₄alkylene; each R^(e) and R^(f) is independently selected from hydrogen,C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogenatom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, and optionally substituted with oxo;each R^(d) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl. In some embodiments, R^(2b) andR^(2c) are both H and R^(2a) is selected from the group consisting ofhalogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₃ haloalkyl, —CN, —OMe and OEt. Insome embodiments, R^(2b) and R^(2c) are both H and R^(2a) is halogen. Insome embodiments, R^(2b) and R^(2c) are both H and R^(2a) is Cl.

In some embodiments, n is 0, 1 or 2 and each R⁵ is independentlyselected from the group consisting of halogen, —CN, —R^(q),—NR^(r)R^(s), and —OR^(r), wherein each R^(r) and R^(s) is independentlyselected from hydrogen, C₁₋₈ alkyl and C₁₋₈ haloalkyl and each R^(q) isindependently selected from the group consisting of C₁₋₈ alkyl and C₁₋₈haloalkyl. In some embodiments, n is 0.

In some embodiments, R^(6a) is H. In some embodiments, m is 0. In someembodiments, m is 1 and R^(b) is selected from the group consisting ofF, C₁₋₄ alkyl, O—R^(u), C₁₋₄ haloalkyl and NR^(u)R^(v), wherein eachR^(u) and R^(v) is independently selected from hydrogen, C₁₋₈ alkyl, andC₁₋₈ haloalkyl. In some embodiments, m is 1 and R^(6b) is F.

In some embodiments,

In some embodiments,

In some embodiments, R⁴ is selected from the group consisting of O—C₁₋₄alkyl, O—C₁₋₆ alkyl-R^(z), C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, —O—C₁₋₄alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀ heteroaryl, wherein the C₆₋₁₀aryl and the C₅₋₁₀ heteroaryl are optionally substituted with 1 to 2R^(z), wherein each R^(z) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —S(O)₂NR^(n)R^(p), threeto seven-membered carbocyclic ring and four to seven-memberedheterocyclic ring wherein the three to seven-membered carbocyclic orfour to seven-membered heterocyclic ring is optionally substituted with1 to 2 R^(t), wherein each R^(t) is independently selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, —CO₂R^(n),—CONR^(n)R^(p), —C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p),—NR^(n)C(O)₂R^(m), —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), and—S(O)₂NR^(n)R^(p). In some embodiments, R⁴ is selected from the groupconsisting of O—C₁₋₄ alkyl, O—C₁₋₆ alkyl-CN, phenyl, pyridinyl, —O—C₁₋₂alkyl-pyridinyl, —O—C₁₋₂ alkyl-pyrimidinyl, —O—C₁₋₂ alkyl-pyridazinyl,and —O—C₁₋₂ alkyl-phenyl, wherein the pyridinyl, phenyl, pyrimidinyl andpyridazinyl is optionally substituted with 1 to 2 R^(z), wherein eachR^(z) is independently selected from the group consisting of halogen,—CN, —CO₂R^(n), —NR^(n)R^(p), —OR^(n), and piperidinyl optionallysubstituted with OH.

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is

In some embodiments, R³ is selected from the group consisting ofNR^(g)R^(h) and C₄₋₆ heterocyclyl wherein the C₄₋₆ heterocyclyl isoptionally substituted with 1 to 3 R^(y), wherein R^(g) is selected fromthe group consisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl, and whereinR^(h) is —C₁₋₈ alkyl substituted with from 1 to 3 substituentsindependently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH, COO—C₁₋₈alkyl, C₅₋₆ heteroaryl, C₅₋₆ heterocyclyl and PO₃H₂, wherein the C₅₋₆heteroaryl and the C₅₋₆ heterocyclyl are optionally substituted with 1to 3 substituents independently selected from OH, B(OH)₂, COOH, SO₂NH₂,CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH,C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkyl CONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, andC₁₋₄alkyl-COOH and wherein the C₅₋₆ heterocyclyl is additionallyoptionally substituted with oxo. In some embodiments, R³ is selectedfrom the group consisting of azetidinyl, pyrrolidinyl and piperidinyl,wherein the azetidinyl, pyrrolidinyl or piperidinyl is linked throughthe nitrogen atom and wherein the azetidinyl, pyrrolidinyl orpiperidinyl is optionally substituted with 1 to 3 R^(y), wherein eachR^(y) is independently selected from the group consisting of —CO₂H,CONOH, PO₃H₂, OH, SO₂NH₂, CONH₂, and COO—C₁₋₈alkyl. In some embodiments,R³ is NHR^(h), wherein R^(h) is —C₁₋₈ alkyl substituted with from 1 to 2substituents independently selected from OH, COOH, CONH₂, PO₃H₂,tetrazolyl, tetrazolonyl, and pyrazolyl. In some embodiments, R³ isselected from the group consisting of:

In some embodiments, R³ is —NR^(g)R^(h). In some embodiments, R^(h)combined with the N to which it is attached is a mono-, di- ortri-peptide comprising 1-3 natural amino acids and 0-2 non-natural aminoacids, wherein

-   -   the non-natural aminoacids have an alpha carbon substituent        selected from the group consisting of C₂₋₄ hydroxyalkyl, C₁₋₃        alkyl-guanidinyl, and C₁₋₄ alkly-heteroaryl,    -   the alpha carbon of each natural or non-natural amino acids are        optionally further substituted with a methyl group, and    -   the terminal moiety of the mono-, di-, or tri-peptide is        selected from the group consisting of C(O)OH, C(O)O—C₁₋₆ alkyl,        and PO₃H₂.

In some embodiments, each natural amino acid of R^(h) is independentlyselected from the group consisting of serine, alanine, glycine, lysine,argining, threonine, phenylalanine, tyrosine, asparatate, asparagine,histidine, and leucine.

In some embodiments, R¹ is phenyl optionally substituted with 1 to 3R^(x), R^(6a) is H, R⁴ is selected from the group consisting of O—C₁₋₄alkyl, O—C₁₋₆ alkyl-CN, phenyl, pyridinyl, —O—C₁₋₂ alkyl-pyridinyl,—O—C₁₋₂ alkyl-pyrimidinyl, —O—C₁₋₂ alkyl-pyridazinyl, and —O—C₁₋₂alkyl-phenyl, wherein the pyridinyl, phenyl, pyrimidinyl and pyridazinylis optionally substituted with 1 to 2 R^(z), wherein each R^(z) isindependently selected from the group consisting of halogen, —CN,—CO₂R^(n), —NR^(n)R^(p), —OR^(n), and piperidinyl optionally substitutedwith OH, and R³ is selected from the group consisting of NR^(g)R^(h) andC₄₋₆ heterocyclyl wherein the C₄₋₆ heterocyclyl is optionallysubstituted with 1 to 3 R^(y), wherein R^(g) is selected from the groupconsisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl, and wherein R^(h) is—C₁₋₈ alkyl substituted with from 1 to 3 substituents independentlyselected from OH, COOH, SO₂NH₂, CONH₂, CONOH, COO—C₁₋₈ alkyl, C₅₋₆heteroaryl, C₅₋₆ heterocyclyl and PO₃H₂, wherein the C₅₋₆ heteroaryl andthe C₅₋₆ heterocyclyl are optionally substituted with 1 to 3substituents independently selected from OH, B(OH)₂, COOH, SO₂NH₂,CONH₂, CONOH, PO₃H₂, COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH,C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkyl CONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, andC₁₋₄alkyl-COOH and wherein the C₅₋₆ heterocyclyl is additionallyoptionally substituted with oxo.

In some embodiments, R¹ is phenyl optionally substituted with 1 or 2R^(x) wherein each R^(x) is independently selected from halogen, C₁₋₈alkyl, O—C₁₋₈ alkyl, O—C₁₋₈haloalkyl, —NR^(a)R^(b), and CN, whereinR^(2b) and R^(2c) are both H, R^(2a) is selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₃ haloalkyl, —CN, —OMe and OEt,R^(6a) is H, m is 0, n is 0, R⁴ is

and R³ is selected from the group consisting of NHR^(h), azetidinyl,pyrrolidinyl and piperidinyl, wherein the azetidinyl, pyrrolidinyl orpiperidinyl is linked through the nitrogen atom and wherein theazetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with 1to 3 R^(y), wherein each R^(y) is independently selected from the groupconsisting of CO₂H, CONOH, PO₃H₂, OH, SO₂NH₂, CONH₂, and COO—C₁₋₈alkyl,and wherein R^(h) is C₁₋₈ alkyl substituted with from 1 to 2substituents independently selected from OH, COOH, CONH₂, PO₃H₂,tetrazolyl, tetrazolonyl, and pyrazolyl. In some embodiment, R² ishalogen.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, is selected from the compounds of Table 2 having an activity of++ or +++. In some embodiments, the compound, or a pharmaceuticallyacceptable salt thereof, is selected from the compounds of Table 2having an activity of +++. In some embodiments, the compound, or apharmaceutically acceptable salt thereof, is selected from the compoundsof Table 2 having an activity of ++. In some embodiments, the compound,or a pharmaceutically acceptable salt thereof, is selected from thecompounds of Table 2 having an activity of +.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, is selected from the compounds of Table 3 having an activity of++ or +++. In some embodiments, the compound, or a pharmaceuticallyacceptable salt thereof, is selected from the compounds of Table 3having an activity of +++. In some embodiments, the compound, or apharmaceutically acceptable salt thereof, is selected from the compoundsof Table 3 having an activity of ++. In some embodiments, the compound,or a pharmaceutically acceptable salt thereof, is selected from thecompounds of Table 3 having an activity of +.

In one aspect, the present disclosure provides compounds having theformula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is selected from the group consisting of C₆₋₁₀ aryl and thienyl,    wherein the C₆₋₁₀ aryl and thienyl are optionally substituted with 1    to 5 R^(x) substituents;-   each R^(x) is independently selected from the group consisting of    halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),    —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(a),    —NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),    —O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X¹—NR^(a)R^(b),    —X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅ and —S(O)₂NR^(a)R^(b), wherein    each X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is independently    selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when    attached to the same nitrogen atom can be combined with the nitrogen    atom to form a five or six-membered ring having from 0 to 2    additional heteroatoms as ring members selected from N, O or S, and    optionally substituted with oxo; each R^(c) is independently    selected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and    C₁₋₈ haloalkyl; and optionally when two R^(x) substituents are on    adjacent atoms, they are combined to form a fused five or    six-membered carbocyclic or heterocyclic ring optionally substituted    with oxo;-   each R^(2a), R^(2b), and R^(2c) is independently selected from the    group consisting of H, halogen, —CN, —R^(d), —CO₂R^(e),    —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e),    —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e),    —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),    —O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),    —X²—CONR^(e)R^(f), —SF₅, and —S(O)₂NR^(e)R^(f), wherein each X² is a    C₁₋₄ alkylene; each R^(e) and R^(f) is independently selected from    hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the    same nitrogen atom can be combined with the nitrogen atom to form a    five or six-membered ring having from 0 to 2 additional heteroatoms    as ring members selected from N, O or S, and optionally substituted    with oxo; each R^(d) is independently selected from the group    consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl;-   R³ is selected from the group consisting of —NR^(g)R^(h) and C₄₋₈    heterocyclyl wherein the C₄₋₈ heterocyclyl is optionally substituted    with 1 to 6 R^(y);-   R^(g) is selected from H or C₁₋₈ alkyl;-   R^(h) is selected from C₁₋₈ alkyl, C₁₋₈ haloalkyl, —C₁₋₈alkyl-C₄₋₈    heterocyclyl, —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, C₁₋₈ alkyl-OH, and C₁₋₈    alkyl-COOH, wherein the C₁₋₈alkyl is optionally substituted with OH    or COOH, wherein the C₅₋₁₀ heteroaryl is optionally substituted with    1 to 3 substituents independently selected from OH, COOH, C₁₋₄alkyl,    C₁₋₄alkyl-OH, and C₁₋₄alkyl-COOH, and wherein the C₄₋₈ heterocyclyl    is optionally substituted with 1 to 3 R^(w) substituents;-   each R^(w) substituent is independently selected from C₁₋₄alkyl,    C₁₋₄alkyl-OH, C₁₋₄alkyl-COOH and oxo;-   each R^(y) is independently selected from the group consisting of    halogen, —CN, —R^(i), —CO₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₄alkyl-OH,    —C(O)R^(j), —OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k),    —NR^(j)—C₁₋₄alkyl-R^(j)C(O)₂R^(k), —NR^(j)C(O)NR^(j)R^(k),    —NR^(j)R^(k), —OR^(j), —S(O)₂NR^(j)R^(k), —O—C₁₋₄alkyl-OR^(j),    —O—C₁₋₄alkyl-NR^(j)R^(k), —O—C₁₋₄alkyl-CO₂R^(j),    —O—C₄alkyl-CONR^(j)R^(k), —C₁₋₄alkyl-OR^(j), —C₁₋₄alkyl-NR^(j)R^(k),    —C₁₋₄alkyl-CO₂R^(j), —C₁₋₄alkyl-CONR^(j)R^(k) and SF₅, wherein the    C₁₋₄alkyl is optionally substituted with OH or CO₂H, wherein each    R^(j) and R^(k) is independently selected from hydrogen, C₁₋₈ alkyl    optionally substituted with OH or CO₂H, and C₁₋₈ haloalkyl    optionally substituted with OH or CO₂H, or when attached to the same    nitrogen atom R^(j) and R^(k) can be combined with the nitrogen atom    to form a five or six-membered ring having from 0 to 2 additional    heteroatoms as ring members selected from N, O or S, and optionally    substituted with oxo; each R^(i) is independently selected from the    group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl    which may be optionally substituted with OH or CO₂H;-   R^(4a) is selected from —C₁₋₄alkyl-C₆₋₁₀aryl and —C₁₋₄alkyl-C₅₋₁₀    heteroaryl, wherein the C₆₋₁₀aryl and the C₅₋₁₀ heteroaryl are    optionally substituted with 1 to 5 R^(z);-   each R^(z) is independently selected from the group consisting of    halogen, —CN, —R^(m), —C₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),    —O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),    —X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅ and    —S(O)₂NR^(n)R^(p), wherein each X³ is a C₁₋₄ alkylene; each R^(n)    and R^(p) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(m) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl; and optionally when two R^(z)    substituents are on adjacent atoms, they are combined to form a    fused five or six-membered carbocyclic or heterocyclic ring    optionally substituted with oxo;-   the subscript n is 0, 1, 2 or 3;-   each R⁵ is independently selected from the group consisting of    halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),    —OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),    —NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),    —O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),    —X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅ and    —S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r)    and R^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(q) is    independently selected from the group consisting of C₁₋₈ alkyl, and    C₁₋₈ haloalkyl.

In some embodiments, compounds, or pharmaceutically acceptable saltsthereof, are provided having the formula (Ia)

In some embodiments, compounds, or pharmaceutically acceptable saltsthereof, are provided having the formula (Ib)

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl and thienyl, wherein the C₆₋₁₀ aryl and thienyl are optionallysubstituted with 1 to 5 R^(x) substituents.

In some embodiments, R¹ is selected from the group consisting of phenyland thienyl, wherein the phenyl and thienyl are optionally substitutedwith 1 to 5 R^(x) substituents. In some embodiments, R¹ is phenylsubstituted with 1 to 5 R^(x) substituents. In some embodiments, R¹ isunsubstituted phenyl.

In some embodiments, each R^(2a), R^(2b), and R^(2c) is independentlyselected from the group consisting of H, halogen, —CN, —R^(d),—NR^(e)R^(f), —OR^(e), —X²—OR^(e), —X²—NR^(e)R^(f), wherein X² is C₁₋₄alkylene; each R^(e) and R^(f) is independently selected from hydrogen,C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogenatom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, and optionally substituted with oxo;each R^(d) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl.

In some embodiments, each R^(2a), R^(2b) and R^(2c) is independentlyselected from the group consisting of halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₁₋₃ haloalkyl, —CN, —OMe and OEt.

In some embodiments, R^(2b) and R^(2c) are both H and R^(2a) is selectedfrom the group consisting of halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₃haloalkyl, —CN, —OMe and OEt.

In some embodiments, R^(2b) and R^(2c) are both H and R^(2a) is halogen.

In some embodiments, R^(2b) and R^(2c) are both H and R^(2a) is Cl.

In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1.In some embodiments, n is 0.

In some embodiments, R³ is selected from the group consisting ofNR^(g)R^(h) and C₄₋₈ heterocyclyl wherein R^(g) is H and wherein theC₄₋₈ heterocyclyl is linked through a N and is optionally substitutedwith 1 to 6 R^(y).

In some embodiments, R³ is selected from the group consisting ofNR^(g)R^(h) and C₄₋₈ heterocyclyl wherein R^(g) is H, R^(h) is selectedfrom —C₁₋₈alkyl-tetrazole, —C₁₋₈alkyl-pyrazole, —C₁₋₈alkyl-pyrrolidine,C₁₋₈ alkyl-OH, and C₁₋₈ alkyl-COOH, wherein the C₁₋₈alkyl is optionallysubstituted with OH or COOH, wherein the tetrazole is optionallysubstituted with OH, wherein the pyrrolidine is optionally substitutedwith oxo, wherein the C₄₋₈ heterocyclyl is azetidine or piperidine andis linked through the N and is optionally substituted with OH or COOH.

In some embodiments, R³ is selected from the group consisting ofNR^(g)R^(h) and C₄₋₈ heterocyclyl wherein R^(g) is H, R^(h) is selectedfrom —C₁₋₄alkyl-tetrazole, —C₁₋₄alkyl-pyrazole, —C₁-4alkyl-pyrrolidine,C₁₋₄ alkyl-OH, and C₁₋₄ alkyl-COOH, wherein the C₁₋₄alkyl is optionallysubstituted with OH or COOH, wherein the tetrazole is optionallysubstituted with OH, wherein the pyrrolidine is optionally substitutedwith oxo, wherein the C₄₋₈ heterocyclyl is azetidine or piperidine andis linked through the N and is optionally substituted with OH or COOH.

In some embodiments, R³ is selected from the group consisting of:

In some embodiments, R³ is selected from the group consisting of:

In some embodiments, R^(4a) is selected from —C₁₋₂alkyl-C₆₋₁₀aryl and—C₁₋₂alkyl-C₅₋₁₀ heteroaryl, wherein the C₆₋₁₀aryl and the C₅₋₁₀heteroaryl are optionally substituted with 1 to 5 R^(z). In someembodiments, R^(4a) is —C₁₋₂alkyl-C₅₋₆ heteroaryl, wherein the C₅₋₆heteroaryl is optionally substituted with 1 to 3 R^(z). In someembodiments, R^(4a) is —CH₂—C₅₋₁₀ heteroaryl optionally substituted with1 to 3 R^(z). In some embodiments, R^(4a) is —CH₂—C₅₋₆ heteroaryloptionally substituted with 1 to 3 R^(z). In some embodiments, R^(4a) is—CH₂-pyridinyl optionally substituted with 1 to 2 R^(z).

In some embodiments, R^(4a) is

In addition to the compounds provided above, pharmaceutically acceptablesalts of those compounds are also provided. In some embodiments, thepharmaceutically acceptable salts are selected from ammonium, calcium,magnesium, potassium, sodium, zinc, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, hydrochloric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, acetic, propionic,isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, arginate, glucuronic acid and galactunoric acids. Insome embodiments, the pharmaceutically acceptable salts are selectedfrom ammonium, calcium, magnesium, potassium, sodium, hydrochloric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, acetic, propionic, isobutyric, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, arginate, glucuronicacid and galactunoric acids. In some embodiments, the pharmaceuticallyacceptable salts are sodium or hydrochloric.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

An ester may be used as a prodrug for the corresponding carboxylic acid.A C₁₋₁₀ alkyl ester or a C₁₋₁₀ haloalkyl ester may be used as a prodrugfor the corresponding carboxylic acid. The following esters may be used:ter-butyl ester, methyl ester, ethyl ester, isopropyl ester. Morespecifically, ester prodrugs may be used as R³ groups such as threonineor serine prodrug esters which are linked to the rest of the moleculethrough their nitrogen. More specifically, the following prodrugs may beused for R³:

More specifically, the following prodrugs may be used for R³:

Pharmaceutical Compositions

In addition to the compounds provided herein, compositions of thosecompounds will typically contain a pharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In another embodiment, a pharmaceutical composition comprising acompound of the present disclosure including a compound of Formula (II),(IIa), (IIb), (I), (Ia), or (Ib) or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient, is provided.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents. In some embodiments, the oneor more additional therapeutic agent is selected from the groupconsisting of an antimicrobial agent, an antiviral agent, a cytotoxicagent, a gene expression modulatory agent, a chemotherapeutic agent, ananti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent,an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, aradiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. In some embodiments, the one or moreadditional therapeutic agent is selected from the group consisting ofone or more of CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239,CCX9664, CCX2553, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765,CCX224, CCX662, CCX650, CCX832, CCX168, and CCX168-M1.

The pharmaceutical compositions for the administration of the compoundsof this disclosure may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self-emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to formosmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) of various average sizes (e.g., PEG400, PEG4000) andcertain surfactants such as cremophor or solutol, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such as mono- ordi-glycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present disclosure are employed. As used herein,topical application is also meant to include the use of mouth washes andgargles.

The compounds of this disclosure may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thedisclosure may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe disclosure, the compound of the disclosure is coupled to a polymeror semipermeable polymer matrix that is formed as a stent or stent-graftdevice.

Methods of Treating Diseases and Disorders

The compounds of the disclosure may be used as immunomodulators. Thecompounds of the disclosure may be used as agonists, antagonists,partial agonists, inverse agonists, inhibitors of PD-1 and/or PD-L1 in avariety of contexts, both in vitro and in vivo. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the PD-1/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used as inhibitors of PD-L1. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the CD80/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used to inhibit the interaction between PD-1 and PD-L1and/or PD-1 and CD80 and/or PD-1 and PD-L2 in vitro or in vivo. In someembodiments, the compounds of the disclosure may be used to inhibitVISTA and/or TIM-3. In some embodiments, the compounds of the disclosuremay be inhibitors of the PD-1/PD-L1 protein protein interaction andinhibitors of VISTA and/or TIM-3. In some embodiments, in addition tobeing inhibitors of the PD-1/PD-L1 protein protein interaction, thecompounds of the disclosure may be inhibitors of CTLA-4 and/or BTLAand/or LAG-3 and/or KLRG-1 and/or 2B4 and/or CD160 and/or HVEM and/orCD48 and/or E-cadherin and/or MHC-II and/or galectin-9 and/or CD86and/or PD-L2 and/or VISTA and/or TIM-3 and/or CD80.

The compounds of the disclosure may be contacted with the receptor theyinteract with, in aqueous solution and under conditions otherwisesuitable for binding of the ligand to the receptor. The receptor may bepresent in suspension (e.g., in an isolated membrane or cellpreparation), in a cultured or isolated cell, or in a tissue or organ.

Preferably, the amount of the compounds of the disclosure contacted withthe receptor should be sufficient to inhibit the PD-1/PD-L1 binding invitro as measured, for example, using an ELISA. The receptor may bepresent in solution or suspension, in a cultured or isolated cellpreparation or within a patient.

In some embodiments, the compounds of the present disclosure are usefulfor restoring and augmenting T cell activation. In some embodiments, thecompounds of the present disclosure are useful for enhancing an immuneresponse in a patient. In some embodiments, the compounds of the presentdisclosure are useful for treating, preventing, or slowing theprogression of diseases or disorders in a variety of therapeutic areas,such as cancer and infectious diseases.

In some embodiments, the compounds of the present disclosure can be usedfor treating patients suffering from conditions that are responsive toPD-1/PD-L1 protein protein interaction modulation.

In some embodiments, a method of modulating an immune response mediatedby the PD-1 signaling pathway in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of thepresent disclosure including a compound of Formula Formula (II), (IIa),(IIb), (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereofor a composition comprising a compound of the present disclosureincluding a compound of Formula (II), (IIa), (IIb), (I), (Ia), or (Ib),or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of enhancing, stimulating, modulatingand/or increasing the immune response in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormula (II), (IIa), (IIb), (I), (Ia), or (Ib), or a pharmaceuticallyacceptable salt thereof or a composition of a compound of the presentdisclosure including a compound of Formula (II), (IIa), (IIb), (I),(Ia), or (Ib), or a pharmaceutically acceptable salt thereof, isprovided.

In some embodiments, a method of inhibiting growth, proliferation, ormetastasis of cancer cells in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure including a compound of Formula (II),(IIa), (IIb), (I), (Ia), or (Ib), or a pharmaceutically acceptable saltthereof or a composition of a compound of the present disclosureincluding a compound of Formula (II), (IIa), (IIb), (I), (Ia), or (Ib),or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of treating a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormula (II), (IIa), (IIb), (I), (Ia), or (Ib), or a pharmaceuticallyacceptable salt thereof or a composition of a compound of the presentdisclosure including a compound of Formula (II), (IIa), (IIb), (I),(Ia), or (Ib), or a pharmaceutically acceptable salt thereof, isprovided.

In some embodiments, the subject suffers from a disease or disorderselected from the group consisting of an infectious disease, a bacterialinfectious disease, a viral infectious disease a fungal infectiousdisease, a solid tumor, a hematological malignancy, an immune disorder,an inflammatory disease, and cancer. In some embodiments, the disease ordisorder is selected from the group consisting of melanoma,glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma,lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma,diffuse large B-cell lymphoma, primary mediastinal large B-celllymphoma, prostate cancer, castration-resistant prostate cancer, chronicmyelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma,synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of softtissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymusneoplasm, cancer of the thyroid gland, cancer of the parathyroid gland,uterine cancer, cancer of the adrenal gland, liver infection, Merkelcell carcinoma, nerve tumor, follicle center lymphoma, colon cancer,Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acuteleukemias including acute myeloid leukemia, chronic myeloid leukemia,acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiplemyeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocularmalignant melanoma, renal cell carcinoma, small-cell lung cancer, lungcancer, mesothelioma, breast cancer, squamous non-small cell lung cancer(SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastriccancer, hepatocellular carcinoma, pancreatic carcinoma, pancreaticcancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of thehead and neck, cancer of the head or neck, gastrointestinal tract,stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D,herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer,rectal cancer, cancer of the anal region, testicular cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the urethra, cancer of the penis, cancer of thebladder, cancer of the kidney, cancer of the ureter, carcinoma of therenal pelvis, neoplasm of the central nervous system (CNS), tumorangiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma,epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillarycarcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cellcarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma,embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cellpapilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma,leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma,lipoma and fibroma.

In some embodiments, a therapeutically effective amount of one or moreadditional therapeutic agents is further administered to the subject. Insome embodiments, the one or more additional therapeutic agents isselected from the group consisting of an antimicrobial agent, anantiviral agent, a cytotoxic agent, a gene expression modulatory agent,a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an immunotherapeutic agent, an anti-hormonal agent, ananti-fibrotic agent, radiotherapy, a radiotherapeutic agent, ananti-neoplastic agent, and an anti-proliferation agent. In someembodiments, the one or more additional therapeutic agent is selectedfrom the group consisting of one or more of CCX354, CCX9588, CCX140,CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025,CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, andCCX168-M1.

In some embodiments, the compounds of the present disclosure may be usedto inhibit an infectious disease. The infectious disease includes but isnot limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, thepathogenic infection by the virus Hepatitis (A, B, and C), herpes virus(e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus),adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus,rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus,HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,rabies virus, JC virus and arboviral encephalitis virus, pathogenicinfection by the bacteria chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, E. coli, legionella,diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax,plague, leptospirosis, and Lyme's disease bacteria, pathogenic infectionby the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.),Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), GenusMucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomycesdermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis andHistoplasma capsulatum, and pathogenic infection by the parasitesEntamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoebasp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosomacruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylusbrasiliensis.

In some embodiments, the compounds of the present disclosure may be usedto inhibit HIV infection, delay AIDS progression, deplete HIV viralreservoir or decrease the severity of symptoms or HIV infection andAIDS.

The compounds of the present disclosure may be used for the treatment ofcancers and precancerous conditions in a subject.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of thedisclosure are preferably administered to a patient (e.g., a human)intravenously, orally or topically. The effective amount may be anamount sufficient to modulate the PD-1/PD-L1 interaction and/or anamount sufficient to reduce or alleviate the symptoms presented by thepatient. Preferably, the amount administered is sufficient to yield aplasma concentration of the compound (or its active metabolite, if thecompound is a pro-drug) high enough to sufficient to modulate thePD-1/PD-L1 interaction. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Combinations

A concomitant medicine comprising the compounds of the presentdisclosure and other drug may be administered as a combinationpreparation in which both components are contained in a singleformulation, or administered as separate formulations. Theadministration by separate formulations includes simultaneousadministration and administration with some time intervals. In the caseof the administration with some time intervals, the compound of thepresent disclosure can be administered first, followed by another drugor another drug can be administered first, followed by the compound ofthe present disclosure. The administration method of the respectivedrugs may be the same or different.

The dosage of the other drug can be properly selected, based on a dosagethat has been clinically used. The compounding ratio of the compound ofthe present disclosure and the other drug can be properly selectedaccording to age and weight of a subject to be administered,administration method, administration time, disorder to be treated,symptom and combination thereof. For example, the other drug may be usedin an amount of 0.01 to 100 parts by mass, based on 1 part by mass ofthe compound of the present disclosure. The other drug may be acombination of two or more kind of arbitrary drugs in a properproportion.

The compounds described herein may be used or combined with one or moretherapeutic agent such as an antimicrobial agent, an antiviral agent, acytotoxic agent, a gene expression modulatory agent, a chemotherapeuticagent, an anti-cancer agent, an anti-angiogenic agent, animmunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent,radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. These therapeutic agents may be in the formsof compounds, antibodies, polypeptides, or polynucleotides.

The compounds described herein may be used or combined with one or moreof a therapeutic antibody, a bispecific antibody and “antibody-like”therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), a virus,an oncolytic virus, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), aCAR (chimeric antigen receptor) T-cell immunotherapeutic agent, or anycombination thereof.

Examples of chemotherapeutics include an alkylation agent, nitrosoureaagent, antimetabolite, anticancer antibiotics, vegetable-originalkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist,aromatase inhibitor, P-glycoprotein inhibitor, platinum complexderivative, other immunotherapeutic drugs and other anticancer drugs.

The compounds described herein may be used or combined with a cancertreatment adjunct, such as a leucopenia (neutropenia) treatment drug,thrombocytopenia treatment drug, antiemetic and cancer pain interventiondrug, concomitantly or in a mixture form.

The compounds described herein may be used or combined with a kinaseinhibitor.

In one embodiment, the compounds of the present disclosure can be usedwith other immunomodulators and/or a potentiating agent concomitantly orin a mixture form. Examples of the immunomodulator include variouscytokines, vaccines and adjuvants. Examples of these cytokines, vaccinesand adjuvants that stimulates immune responses include but not limitedto GM-CSF, M-CSF, G-CSF, interferon-a, beta, or gamma, IL-1, IL-2, IL-3,IL-12, Poly (I:C) and CPG. The potentiating agents includecyclophosphamide and analogs of cyclophosphamide, anti-TGF and imatinib(Gleevac), a mitosis inhibitor, such as paclitaxel, Sunitinib (Sutent)or other antiangiogenic agents, an aromatase inhibitor, such asletrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesisinhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists,and IL-18 antagonists.

In some embodiments, the compounds described herein may be used orcombined with one or more modulator of CCR1, CCR2, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, themodulator is an antagonist.

In some embodiments, the compounds described herein may be used orcombined with one or more of CCX354, CCX9588, CCX140, CCX872, CCX598,CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, and CCX168-M1.

Dosage

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving the PD-1/PD-L1 interaction (about0.5 mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravaneously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

In another aspect of the disclosure, the compounds of the disclosure canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. The compounds of the disclosure may also be used aspositive controls in assays for PD-1/PD-L1 interaction activity, i.e.,as standards for determining the ability of a candidate agent to bind toPD-1 and/or PD-L1, or as radiotracers for positron emission tomography(PET) imaging or for single photon emission computerized tomography(SPECT).

Also within the scope of the present disclosure are kits comprising acompound of the present disclosure or pharmaceutically acceptable saltsthereof and instructions for use. The kit can further contain at leastone additional reagent. Kits typically include a label indicating theintended use of the contents of the kit. The term label includes anywriting, or recorded material supplied on or with the kit, or whichotherwise accompanies the kit.

General Synthetic Procedures

The embodiments are also directed to processes and intermediates usefulfor preparing the subject compounds or pharmaceutically acceptable saltsthereof.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups.

Representative syntheses of compounds of the present disclosure aredescribed in the scheme below, and the particular examples that follow.Schemes 1 and 2 are provided as further embodiment of the disclosure andillustrate general methods which were used to prepare compounds of thepresent disclosure including compounds of Formula (II), (IIa), (IIb),(I), (Ia), or (Ib), and which can be used to prepare additionalcompounds having the Formula (II), (IIa), (Ib), (I), (Ia), or (Ib). Themethodology is compatible with a wide variety of functionalities.

Coupling at the 4-position of the indane ring can be accomplished viatransition metal mediated coupling using the appropriate 4-bromoindanoland a boronic acid or ester. In the subsequent step, the ether bond canbe formed using appropriate reagents such as triphenyl phosphine anddiisopropyl or diethyl azodicarboxylate. Alkylation of the phenolintermediate can be achieved using the corresponding alkyl halide ormesylate reagent. The following reductive amination can be accomplishedusing an appropriate primary or secondary amine (shown as H₂N—R′) and areducing agent such as sodium cyanoborohydride or sodiumtriacetoxyborohydride in presence of a mild acid such as acetic acid.The amine group added in the reductive amination is shown as R³ in thediagram above. The transformations shown in Scheme 1 may be performed inany order that is compatible with the functionality of the particularpendant groups.

The 4-Bromoindanone compound can be enantioselectively reduced to itsoptically pure 4-bromoindanol derivative using a chiral reducing agentcontaining boron. Coupling at the 4-position of the indane ring can beaccomplished via transition metal mediated coupling using the4-bromoindanol and boronic acid or ester. In the subsequent step, theether bond can be formed using reagents such as triphenyl phosphine anddiisopropyl or diethyl azodicarboxylate (in this case, the reactionleads to an inversion of configuration, however, some racemization wasobserved). Alkylation of the phenol intermediate can be achieved usingthe appropriate alkyl halide or mesylate reagent. The reductiveamination can be accomplished using the appropriate primary or secondaryamine (shown as H₂N—R′) and a reducing agent such as sodiumcyanoborohydride or sodium triacetoxyborohydride in presence of a mildacid such as acetic acid. The amine group added in the reductiveamination is shown as R³ in the diagram above. The transformations shownin Scheme 2 may be performed in any order that is compatible with thefunctionality of the particular pendant groups. The indanol derivativeobtained in the first step having the opposite stereocenter to thestereocenter represented in Scheme 2 can be prepared using theappropriate chiral reducing agent and the rest of the synthetic steps inthe sequence can be performed without any changes to obtain finalcompounds with the opposite stereocenter.

As an example, enrichment of optical purity of chiral intermediates canbe achieved as described in Scheme 3.

EXAMPLES

The following Examples illustrate various methods of making compounds ofthis disclosure including compounds of Formula (II), (IIa), (IIb), (I),(Ia), or (Ib). The following examples are offered to illustrate, but notto limit the claimed disclosure.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge. In the examples, a single m/z value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol or CH₃CN at 0.1 mg/mL and 1 microliter was infused with thedelivery solvent into the mass spectrometer, which scanned from 100 to1000 Daltons. All compounds could be analyzed in the positive ornegative ESI mode, using acetonitrile/water with 1% formic acid as thedelivery solvent.

The following abbreviations are used in the Examples and throughout thedescription of the disclosure: TLC means Thin layer chromatography.

Compounds within the scope of this disclosure can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisdisclosure, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed unless a specific enantiomer is specified.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-(4-phenylindan-1-yl)oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of 4-bromoindan-1-ol (500 mg, 2.34 mmol) in DME(10 mL) was added phenylboronic acid (286 mg, 2.34 mmol), K₂CO₃ (969 mg,7.02 mmol) and the resulting suspension was bubbled with nitrogen gasfor one minute. Pd(PPh₃)₄ (271 mg, 0.234 mmol) was then added and thereaction mixture was bubbled with nitrogen gas for an additional minuteand stirred at 80° C. overnight. The reaction mixture was diluted withEtOAc (30 mL), washed with water (30 mL), brine (30 mL), dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 20% EtOAc in hexanes) to obtain4-phenylindan-1-ol. MS: (ES) m/z calculated for C₁₅H₁₃ [M-OH]⁻ 193.1,found 193.1.

Step b: To a solution of 4-phenylindan-1-ol (418 mg, 1.99 mmol) in THE(5 mL) at room temperature was added 5-chloro-2,4-dihydroxy-benzaldehyde(309 mg, 1.791 mmol) and PPh₃ (521 mg, 1.99 mmol). The resultingsolution was cooled to to 0° C. before DIAD (402 mg, 1.99 mmol) in THE(2 mL) was added slowly dropwise. The resulting solution was allowed towarm to room temperature with stirring. After 12 h at room temperature,the volatiles were evaporated in vacuo. The resulting residue waspurified by flash chromatography (SiO₂, 50% EtOAc in hexanes) to obtain5-chloro-2-hydroxy-4-(4-phenylindan-1-yl)oxy-benzaldehyde. MS: (ES) m/zcalculated for C₂₂H₁₆ClO₃ [M−H]⁺ 360.1, found 360.0 (negative mode).

Step c: To a solution of5-chloro-2-hydroxy-4-(4-phenylindan-1-yl)oxy-benzaldehyde (100 mg, 0.274mmol) in DMF (5 mL) was added 5-(bromomethyl)pyridine-3-carbonitrile(108 mg, 0.549 mmol) followed by Cs₂CO₃ (178 mg, 0.549 mmol). Theresulting suspension was then stirred at 65° C. for 2 h. The reactionmixture was diluted with EtOAc (20 mL), washed with water (20 mL), dried(MgSO₄), concentrated in vacuo. The crude residue was purified by flashchromatography (SiO₂, 80% EtOAc in hexanes) to obtain5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₉H₂₂ClN₂O₃ [M+H]⁺ 481.1, found 481.3.

Step d: To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, xx mmol) in DMF (2 mL) was added(2S)-2-amino-3-hydroxy-propanoic acid (100 mg) and Na(OAc)₃BH (100 mg,xx mmol), and the resulting suspension was stirred at room temperatureovernight. The reaction mixture was diluted with 2:1 CHCl₃/IPA (30 mL),washed with water (15 mL), dried (MgSO₄), and concentrated in vacuo. Thecrude residue was purified by reverse phase preparative HPLC (CH₃CN—H₂Owith 0.1% TFA) to obtain(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-(4-phenylindan-1-yl)oxy-phenyl]methylamino]-3-hydroxy-propanoicacid. MS: (ES) m/z calculated for C₃₂H₂₉CN₃O₅ [M+H]⁺ 570.2, found 570.1.¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J=2.1 Hz, 1H), 8.92 (d, J=2.0Hz, 1H), 8.43 (t, J=2.1 Hz, 1H), 7.53 (s, 1H), 7.50-7.28 (m, 8H), 7.11(d, J=1.6 Hz, 1H), 6.02 (dd, J=6.4, 4.2 Hz, 1H), 5.45-5.33 (m, 2H), 4.35(q, J=13.1 Hz, 2H), 4.01 (s, 3H), 3.34-3.14 (m, 1H), 2.98 (ddd, J=16.2,8.2, 5.3 Hz, 1H), 2.56 (dq, J=13.7, 6.7 Hz, 1H), 2.21-2.10 (m, 1H).

Example 2: Synthesis of(3S)-4-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-(4-phenylindan-1-yl)oxy-phenyl]methylamino]-3-hydroxy-butanoicacid

To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(120 mg, 0.25 mmol) in DMF (3 mL) was added(3S)-4-amino-3-hydroxy-butanoic acid (200 mg, 1 mmol) and AcOH (100 μL),followed by NaCNBH₃ (100 mg, 1.58 mmol). The resulting suspension wasstirred at room temperature overnight. The reaction mixture was dilutedwith 2:1 CHCl₃/IPA (30 mL), washed with water (15 mL), dried (MgSO₄),and concentrated in vacuo. The crude was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain(3S)-4-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-(4-phenylindan-1-yl)oxy-phenyl]methylamino]-3-hydroxy-butanoicacid. MS: (ES) m/z calculated for C₃₃H₃₁ClN₃O₅ [M+H]⁺ 584.2, found584.1. ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J=2.2 Hz, 1H), 8.93 (d,J=2.0 Hz, 1H), 8.44-8.34 (m, 1H), 7.57-7.28 (m, 9H), 7.11 (d, J=1.0 Hz,1H), 6.01 (dd, J=6.4, 4.2 Hz, 1H), 5.51-5.34 (m, 2H), 4.83-4.68 (m, 1H),4.32-4.17 (m, 2H), 3.27-3.14 (m, 2H), 3.05-2.92 (m, 2H), 2.58-2.48 (m,3H), 2.19-2.11 (m, 1H).

Example 3: Synthesis of(3S)-4-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid

Step a: To a solution of 4-bromoindan-1-one (3 g, 2.34 mmol) in DME (15mL) was added phenylboronic acid (1.73 g, 14.2 mmol) and K₂CO₃ (5.9 g,42.6 mmol). The resulting suspension was bubbled with nitrogen gas forone minute before Pd(PPh₃)₄ (1.64 g, 1.42 mmol) was added. The reactionmixture was bubbled with nitrogen gas for an additional minute andsubsequently stirred at 75° C. overnight. The mixture was diluted withEtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO₄),and concentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 50% EtOAc in hexanes) to obtain4-phenylindan-1-one. MS: (ES) m/z calculated for C₁₅H₁₃O [M+H]⁺ 209.1,found 209.3.

Step b: To (S)-(−)-2-Methyl-CBS (Corey-Bakshi-Shibata)-oxazaborolidine(900 μL, 0.887 mmol, 1 M in THF) was added BH₃.DMS (443 μL, 0.887 mmol,2 M solution in THF) under nitrogen atmosphere and the reaction mixturewas stirred at room temperature for 10 minutes. The reaction was dilutedwith CH₂Cl₂ (5 mL). followed by the addition of BH₃.DMS (16.3 mL, 32.52mmol, 2 M solution in THF). The mixture was cooled to −20° C. before4-phenylindan-1-one (1.23 g, 5.913 mmol) in CH₂Cl₂ (5 mL) was addeddropwise. After stirring for 2 h at −20° C., the reaction was carefullyquenched by the addition of MeOH (10 mL). The volatiles were removed invacuo and the crude product was purified by flash chromatography (SiO₂,50% EtOAc in hexanes) to obtain (1R)-4-phenylindan-1-ol (er: 94/6). Theenantiomeric ratio was determined by ¹⁹F NMR analysis of thecorresponding (S)-Mosher's ester. MS: (ES) m/z calculated for C₁₅H₁₃[M-OH]⁻ 193.1, found 193.1.

Step c: To a solution of (1R)-4-phenylindan-1-ol (840 mg, 4.0 mmol) inTHF (10 mL) at room temperature was added5-chloro-2,4-dihydroxy-benzaldehyde (690 mg, 4.0 mmol), followed by PPh₃(1.05 g, 4 mmol), and the resulting solution was cooled to 0° C. DIAD(808 mg, 4.0 mmol) in THF (3 mL) was added slowly dropwise and theresulting solution was allowed to warm to room temperature withstirring. After 12 h at room temperature, the volatiles were evaporatedin vacuo, The crude was purified by flash chromatography (SiO₂, 50%EtOAc in hexanes) to obtain5-chloro-2-hydroxy-4-[(1S)-4-phenylindan-1-yl]oxy-benzaldehyde. MS: (ES)m/z calculated for C₂₂H₁₆ClO₃ [M+H]⁺ 363.1, found 363.0. Approximately22% of racemization was observed during the reaction and theenantiomeric ratio (er) of the obtained product was ˜3.5:1. All thefinal compounds described in examples 10, 12, 13, 14 and 15 wereprepared using this intermediate with er: 3.5:1.

Step d: To a solution of5-chloro-2-hydroxy-4-[(1S)-4-phenylindan-1-yl]oxy-benzaldehyde (178 mg,0.489 mmol) in DMF (5 mL) was added5-(bromomethyl)pyridine-3-carbonitrile (192 mg, 0.978 mmol) and Cs₂CO₃(318 mg, 0.978 mmol) and the resulting suspension was then stirred at75° C. for 2 h. The reaction mixture was diluted with EtOAc (30 mL),washed with water (20 mL), dried (MgSO₄), and concentrated in vacuo. Thecrude was purified by flash chromatography (SiO₂, 80% EtOAc in hexanes)to obtain5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile,er: ˜3.5:1. MS: (ES) m/z calculated for C₂₉H₂₂ClN₂O₃ [M+H]⁺ 481.1, found481.1.

Step e: To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(66 mg, 0.1375 mmol) in DMF (4 mL) was added(2S)-2-amino-3-hydroxy-propanoic acid (33 mg, 0.275 mmol), AcOH (20 μL,0.1375 mmol), followed by NaCNBH₃ (20 mg, 0.206 mmol). The resultingmixture was stirred at room temperature overnight before it was dilutedwith 2:1 CHCl₃/IPA (30 mL), washed with water (15 mL), dried (MgSO₄),and concentrated in vacuo. The crude was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain(3S)-4-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid, dr (diastereomeric ratio): 3.5:1. MS: (ES) m/z calculated forC₃₃H₃₁CN₃O₅ [M+H]⁺ 584.2, found 584.1. ¹H NMR (400 MHz, Methanol-d₄) δ8.99 (d, J=2.2 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.44-8.34 (m, 1H),7.57-7.28 (m, 9H), 7.11 (d, J=1.0 Hz, 1H), 6.01 (dd, J=6.4, 4.2 Hz, 1H),5.51-5.34 (m, 2H), 4.83-4.68 (m, 1H), 4.32-4.17 (m, 2H), 3.27-3.14 (m,2H), 3.05-2.92 (m, 2H), 2.58-2.48 (m, 3H), 2.19-2.11 (m, 1H).

Example 4: Synthesis of(3S)-4-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1R)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid

Step a: To (R)-(+)-2-methyl-CBS (Corey-Bakshi-Shibata)-oxazaborolidine(900 μL, 0.887 mmol, 1 M solution in THF) under nitrogen atmosphere wasadded BH₃-DMS (443 μL, 0.887 mmol, 2 M solution in THF) at roomtemperature and stirred for 10 minutes. The reaction mixture was dilutedwith CH₂Cl₂ (5 mL) and BH₃.DMS (16.3 mL, 32.52 mmol, 2 M solution inTHF) was added before cooling to −20° C. 4-Phenylindan-1-one (1.23 g,5.913 mmol) in CH₂Cl₂ (5 mL) was then added drop wise and the mixturewas stirred for 2 h at −20° C. The reaction was quenched by the carefuladdition of MeOH (10 mL). The volatiles were removed in vacuo and theresulting crude was purified by flash chromatography (SiO₂, 50% EtOAc inhexanes) to obtain (1S)-4-phenylindan-1-ol (er 92/8). The enantiomericratio was determined by ¹⁹F NMR analysis of the corresponding(S)-Mosher's ester. MS: (ES) m/z calculated for C₁₅H₁₃ [M-OH]⁻ 193.1,found 193.1.

Step b: To a solution of (1S)-4-phenylindan-1-ol (840 mg, 4 mmol) in THF(10 mL) at room temperature was added5-chloro-2,4-dihydroxy-benzaldehyde (690 mg, 4 mmol) followed by PPh₃(1.05 g, 4 mmol). The resulting solution was cooled to 0° C. before DIAD(808 mg, 4 mmol) in THE 3 mL) was added slowly dropwise. The solutionwas allowed warm to room temperature and stirred for 12 h. The volatileswere removed in vacuo and the crude was purified by flash chromatography(SiO₂, 50% EtOAc in hexanes) to obtain5-chloro-2-hydroxy-4-[(1R)-4-phenylindan-1-yl]oxy-benzaldehyde. MS: (ES)m/z calculated for C₂₂H₁₆ClO₃ [M−H]⁻ 363.1, found 363.0 Approximately17% of racemization was observed during the reaction and theenantiomeric ratio of the obtained product was ˜5:1.

Step c: To a solution of5-chloro-2-hydroxy-4-[(1R)-4-phenylindan-1-yl]oxy-benzaldehyde (340 mg,0.934 mmol) in DMF (5 mL) was added5-(bromomethyl)pyridine-3-carbonitrile (366 mg, 1.868 mmol), followed byCs₂CO₃ (607 mg, 1.868 mmol). The resulting suspension was then stirredat 75° C. for 2 h. Reaction mixture was diluted with EtOAc (30 mL),washed with water (20 mL), dried (MgSO₄), and concentrated in vacuo. Thecrude was purified by flash chromatography (SiO₂, 80% EtOAc in hexanes)to obtain5-[[4-chloro-2-formyl-5-[(1R)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile,er ˜5:1. MS: (ES) m/z calculated for C₂₉H₂₂CN₂O₃ [M+H]⁺ 481.1, found481.0.

Step d: To a solution of5-[[4-chloro-2-formyl-5-[(1R)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(304 mg, 0.633 mmol) in DMF (5 mL) was added(2S)-2-amino-3-hydroxy-propanoic acid (301 mg, 2.53 mmol) and AcOH (152μL, 2.53 mmol), followed by NaCNBH₃ (159 mg, 2.53 mmol), and theresulting suspension was stirred at room temperature overnight. Thereaction mixture was diluted with 2:1 CHCl₃/IPA (30 mL), washed withwater (15 mL), dried (MgSO₄), and concentrated in vacuo. The crude waspurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtain(3S)-4-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1R)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid, dr ˜5:1. MS: (ES) m/z calculated for C₃₃H₃₁ClN₃O₅ [M+H]⁺ 584.2,found 584.2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J=2.2 Hz, 1H),8.93 (d, J=2.0 Hz, 1H), 8.44-8.34 (m, 1H), 7.57-7.28 (m, 9H), 7.11 (d,J=1.0 Hz, 1H), 6.01 (dd, J=6.4, 4.2 Hz, 1H), 5.51-5.34 (m, 2H),4.83-4.68 (m, 1H), 4.32-4.17 (m, 2H), 3.27-3.14 (m, 2H), 3.05-2.92 (m,2H), 2.58-2.48 (m, 3H), 2.19-2.11 (m, 1H).

Example 5: Synthesis of5-[[4-chloro-5-(4-phenylindan-1-yl)oxy-2-[(1H-tetrazol-5-ylmethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added 1H-tetrazol-5-ylmethanamine(100 mg, 0.99 mmol), AcOH (100 μL, 1.66 mmol) followed by Na(OAc)₃BH(100 mg, 0.47 mmol) and the resulting suspension was stirred at roomtemperature overnight. The reaction mixture was diluted with 2:1CHCl₃/IPA (30 mL) and washed with water (15 mL), dried (MgSO₄),concentrated in vacuo and purified by reverse phase preparative HPLC(CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-5-(4-phenylindan-1-yl)oxy-2-[(1H-tetrazol-5-ylmethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₃₁H₂₇ClN₇O₂ [M+H]⁺ 564.2, found 564.2. ¹HNMR (400 MHz, Methanol-d₄) δ 8.94 (dd, J=2.9, 2.1 Hz, 2H), 8.38 (t,J=2.1 Hz, 1H), 7.53 (s, 1H), 7.50-7.26 (m, 8H), 7.11 (s, 1H), 6.01 (dd,J=6.5, 4.3 Hz, 1H), 5.38 (d, J=1.8 Hz, 2H), 4.64-4.55 (m, 2H), 4.40 (s,2H), 3.43-3.14 (m, 1H), 2.98 (ddd, J=16.2, 8.2, 5.3 Hz, 1H), 2.55 (ddt,J=14.2, 8.2, 6.1 Hz, 1H), 2.14 (ddt, J=13.3, 8.2, 4.8 Hz, 1H).

Example 6: Synthesis of5-[[4-chloro-2-[(2-hydroxyethylamino)methyl]-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added 2-aminoethanol (100 μL, 1.64mmol) followed by Na(OAc)₃BH (100 mg, 0.47 mmol) and the resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/IPA (30 mL) and washed with water (15mL), dried (MgSO₄), concentrated in vacuo and purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-2-[(2-hydroxyethylamino)methyl]-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₃₁H₂₉ClN₃O₃ [M+H]⁺ 526.2, found 526.2.

Example 7: Synthesis of(2S)-1-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-(4-phenylindan-1-yl)oxy-phenyl]methyl]piperidine-2-carboxylicacid

To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added (2S)-piperidine-2-carboxylicacid (100 mg, 0.775 mmol) followed by Na(OAc)₃BH (100 mg, 0.47 mmol) andthe resulting suspension was stirred at room temperature overnight. Thereaction mixture was diluted with 2:1 CHCl₃/IPA (30 mL) and washed withwater (15 mL), dried (MgSO₄), concentrated in vacuo and purified byreverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) to(2S)-1-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-(4-phenylindan-1-yl)oxy-phenyl]methyl]piperidine-2-carboxylicacid. MS: (ES) m/z calculated for C₃₅H₃₃CN₃O₄ [M+H]⁺ 594.2, found 594.1.¹H NMR (400 MHz, Methanol-d₄) δ 9.00-8.91 (m, 2H), 8.42 (d, J=1.9 Hz,1H), 7.57 (s, 1H), 7.51-7.29 (m, 9H), 7.13 (d, J=3.5 Hz, 1H), 6.03 (dd,J=6.4, 4.3 Hz, 1H), 5.40 (d, J=2.9 Hz, 2H), 4.89-4.68 (m, 1H), 4.46 (d,J=13.6 Hz, 1H), 4.38 (s, 1H), 3.99 (s, 1H), 3.31-3.13 (m, 1H), 3.07-2.92(m, 2H), 2.57 (dt, J=13.8, 7.5 Hz, 1H), 2.31 (s, 1H), 2.14 (tt, J=8.8,4.6 Hz, 1H), 1.86 (s, 2H), 1.61 (s, 2H).

Example 8: Synthesis of5-[[2-(azetidin-1-ylmethyl)-4-chloro-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added azetidine (100 μL, 1.49mmol), AcOH (100 μL, 1.64 mmol) followed by Na(OAc)₃BH (100 mg, 0.47mmol) and the resulting suspension was stirred at room temperatureovernight. The reaction mixture was diluted with 2:1 CHCl₃/IPA (30 mL)and washed with water (15 mL), dried (MgSO₄), concentrated in vacuo andpurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtain5-[[2-(azetidin-1-ylmethyl)-4-chloro-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₃₂H₂₉ClN₃O₂ [M+H]⁺ 522.2, found 522.1. ¹HNMR (400 MHz, Methanol-d₄) δ 8.96 (dd, J=15.9, 2.1 Hz, 2H), 8.40 (td,J=2.0, 0.6 Hz, 1H), 7.53-7.26 (m, 9H), 7.10 (s, 1H), 6.00 (dd, J=6.5,4.2 Hz, 1H), 5.41 (s, 2H), 4.37 (s, 2H), 4.25-4.04 (m, 4H), 3.36-3.13(m, 1H), 2.97 (ddd, J=16.2, 8.2, 5.3 Hz, 1H), 2.60-2.47 (m, 2H), 2.41(dt, J=12.0, 5.8 Hz, 1H), 2.19-2.06 (m, 1H).

Example 9: Synthesis of5-[[4-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile(140 mg, 0.292 mmol) in DMF (3 mL) was added azetidin-3-ol hydrochloride(127 mg, 1.2 mmol), Et₃N (406 μL, 2.92 mmol), AcOH (200 μL, 2.92 mmol)followed by Na(OAc)₃BH (186 mg, 0.876 mmol) and the resulting suspensionwas stirred at room temperature overnight. The reaction mixture wasdiluted with 2:1 CHCl₃/IPA (30 mL) and washed with water (15 mL), dried(MgSO₄), concentrated in vacuo and purified by reverse phase preparativeHPLC (CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]-5-(4-phenylindan-1-yl)oxy-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₃₂H₂₉ClN₃O₃ [M+H]⁺ 538.2, found 538.1. ¹HNMR (400 MHz, Methanol-d₄) δ 8.96 (dd, J=19.5, 2.0 Hz, 2H), 8.41 (d,J=10.4 Hz, 1H), 7.54-7.28 (m, 9H), 7.11 (d, J=7.4 Hz, 1H), 6.01 (t,J=5.4 Hz, 1H), 5.41 (s, 2H), 4.67 (s, 1H), 4.57 (t, J=6.6 Hz, 1H),4.46-4.29 (m, 4H), 4.02-3.90 (m, 2H), 3.34-3.13 (m, 1H), 2.98 (ddd,J=16.2, 8.2, 5.4 Hz, 1H), 2.58-2.50 (m, 1H), 2.18-2.08 (m, 1H).

Example 10: Synthesis of5-[[4-chloro-2-[[2-(5-oxo-1H-tetrazol-4-yl)ethylamino]methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile

Step a: Oxalyl chloride (5.7 mL, 67.26 mmol) was slowly added to3-(benzyloxycarbonylamino)propanoic acid (5 g, 22.42 mmol) dissolved inCH₂Cl₂ (75 mL) at room temperature followed by few drops of DMF tocatalyze the reaction (gas evolution was observed immediately). After 2h, the reaction mixture was concentrated in vacuo. Additional CH₂Cl₂ (50mL) was added and concentrated in vacuo followed by drying on highvacuum pump to obtain benzyl N-(3-chloro-3-oxo-propyl)carbamate whichwas used as such in the next step without any further purification. MS(after quenching the acid chloride with MeOH): (ES) m/z calculated forC₁₂H₁₅NO₄Na [Methyl ester, M+Na]⁺ 260.1, found 260.3.

Step b: A safety notice for the procedure: Azide compounds arepotentially explosive. This reaction was performed behind a blastshield. TMSN₃ (2.4 mL, 18 mmol) was slowly added to benzylN-(3-chloro-3-oxo-propyl)carbamate (723 mg, 6 mmol) at room temperature(gas evolution was observed). The resulting reaction mixture was heatedand stirred overnight at 100° C. Volatiles were removed in vacuo and thecrude product was directly purified by flash chromatography (SiO₂, 80%EtOAc in hexanes) to obtain benzylN-[2-(5-oxo-1H-tetrazol-4-yl)ethyl]carbamate. MS: (ES) m/z calculatedfor C₁₁H₁₄N₅O₃ [M+H]⁺ 264.1, found 264.4 (also observed significant peakfor [M+Na]⁺).

Step c: To benzyl N-[2-(5-oxo-1H-tetrazol-4-yl)ethyl]carbamate (250 mg,0.95 mmol) in MeOH (10 mL) was added 10% Pd/C (200 mg) in a Parr shakerflask, the resulting suspension was purged twice with hydrogen gas andagitated at room temperature under hydrogen gas (60 psi) for one hour.The reaction mixture was filtered through a pad of Celite, washed withMeOH (15 mL) and concentrated in vacuo to obtain4-(2-aminoethyl)-1H-tetrazol-5-one which was used as such in the nextstep without any further purification. MS: (ES) m/z calculated forC₃H₈N₅O [M+H]⁺ 130.1, found 130.3.

Step d: To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(100 mg, 0.208 mmol) in DMF (4 mL) was added4-(2-aminoethyl)-1H-tetrazol-5-one (50 mg, 0.387 mmol), AcOH (50 μL,0.53 mmol) followed by Na(OAc)₃BH (90 mg, 0.424 mmol) and the resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/IPA (30 mL) and washed with water (15mL), dried (MgSO₄) concentrated in vacuo and purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-2-[[2-(5-oxo-1H-tetrazol-4-yl)ethylamino]methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile,er: ˜3.5:1. MS: (ES) m/z calculated for C₃₂H₂₉ClN₇O₃ [M+H]⁺ 594.2, found594.5. ¹H NMR (400 MHz, Methanol-d₄) δ 8.96 (dd, J=27.3, 2.0 Hz, 2H),8.47-8.38 (m, 1H), 7.57-7.39 (m, 5H), 7.41-7.25 (m, 4H), 7.10 (s, 1H),6.00 (dd, J=6.4, 4.2 Hz, 1H), 5.45-5.40 (m, 2H), 4.39-4.30 (m, 4H),3.58-3.47 (m, 2H), 3.24-3.13 (m, 1H), 2.98 (td, J=8.1, 5.3 Hz, 1H),2.58-2.47 (m, 1H), 2.18-2.07 (m, 1H).

Example 11: Synthesis of(2S)-2-[[5-chloro-4-(4-phenylindan-1-yl)oxy-2-(3-pyridylmethoxy)phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of 4-bromoindan-1-ol (5.3 g, 24.91 mmol) in THF(30 mL) at room temperature was added5-chloro-2,4-dihydroxy-benzaldehyde (4.3 g, 24.91 mmol) followed by PPh₃(6.5 g, 24.91 mmol) and the resulting solution was cooled in anice-bath. DIAD (5.03 g, 24.91 mmol) in THF (10 mL) was added slowlydropwise at 0° C. and the resulting solution was allowed to warm to roomtemperature with stirring. After 12 h at room temperature, volatileswere evaporated in vacuo, the resulting residue was purified by flashchromatography (SiO₂, 50% EtOAc in hexanes) to obtain4-(4-bromoindan-1-yl)oxy-5-chloro-2-hydroxy-benzaldehyde. MS: (ES) m/zcalculated for C₁₆H₁₈BrClO₃ [M−H]⁺ 365.0, found 364.9 (negative mode).

Step b: To a solution of4-(4-bromoindan-1-yl)oxy-5-chloro-2-hydroxy-benzaldehyde (250 mg, 0.683mmol) in DMF (3 mL) was added 3-(chloromethyl)pyridine hydrochloride(225 mg, 1.37 mmol) followed by Cs₂CO₃ (444 mg, 1.37 mmol). Theresulting suspension was stirred at 75° C. for 2 h. The reaction mixturewas diluted with EtOAc (20 mL) and washed with water (20 mL), dried(MgSO₄), concentrated in vacuo and purified by flash chromatography(SiO₂, 80% EtOAc in hexanes) to obtain4-(4-bromoindan-1-yl)oxy-5-chloro-2-(3-pyridylmethoxy)benzaldehyde. MS:(ES) m/z calculated for C₂₂H₁₈BrClNO₃ [M+H]⁺ 458.0, found 458.4.

Step c: To a solution of4-(4-bromoindan-1-yl)oxy-5-chloro-2-(3-pyridylmethoxy)benzaldehyde (312mg, 0.683 mmol) in DME (5 mL) was added phenylboronic acid (150 mg, 1.02mmol), K₂CO₃ (283 mg, 2.05 mmol) and the resulting suspension wasbubbled with nitrogen gas for one minute. Pd(PPh₃)₄ (80 mg, 0.0683 mmol)was then added, bubbled the reaction mixture with nitrogen gas foradditional minute and stirred at 80° C. overnight. The reaction mixturewas diluted with EtOAc (20 mL), washed with water (20 mL), brine (20mL), dried (Na₂SO₄) and concentrated in vacuo. The obtained crudeproduct was purified by flash chromatography (SiO₂, 80% EtOAc inhexanes) to obtain5-chloro-4-(4-phenylindan-1-yl)oxy-2-(3-pyridylmethoxy)benzaldehyde. MS:(ES) m/z calculated for C₂₈H₂₃ClNO₃ [M+H]⁺ 456.1, found 456.2.

Step d: To a solution of5-chloro-4-(4-phenylindan-1-yl)oxy-2-(3-pyridylmethoxy)benzaldehyde (55mg) in DMF (3 mL) was added (2S)-2-amino-3-hydroxy-propanoic acid (100mg) followed by Na(OAc)₃BH (100 mg) and the resulting suspension wasstirred at room temperature overnight. The reaction mixture was dilutedwith 2:1 CHCl₃/IPA (30 mL) and washed with water (15 mL), dried (MgSO₄)concentrated in vacuo and purified by reverse phase preparative HPLC(CH₃CN—H₂O with 0.1% TFA) to obtain(2S)-2-[[5-chloro-4-(4-phenylindan-1-yl)oxy-2-(3-pyridylmethoxy)phenyl]methylamino]-3-hydroxy-propanoicacid. MS: (ES) m/z calculated for C₃₁H₃₀ClN₂O₅ [M+H]⁺ 545.2, found545.4. ¹H NMR (400 MHz, Methanol-d₄) δ 8.97 (d, J=2.0 Hz, 1H), 8.74 (d,J=5.3 Hz, 1H), 8.49 (d, J=8.1 Hz, 1H), 7.86 (dd, J=8.0, 5.4 Hz, 1H),7.54 (s, 1H), 7.50-7.38 (m, 5H), 7.41-7.26 (m, 4H), 7.13 (d, J=1.4 Hz,1H), 6.01 (dd, J=6.5, 4.3 Hz, 1H), 5.45 (t, J=1.9 Hz, 2H), 4.43-4.29 (m,2H), 4.02 (s, 2H), 3.20 (ddd, J=16.4, 8.3, 5.8 Hz, 1H), 2.99 (td, J=8.1,5.3 Hz, 1H), 2.61-2.50 (m, 1H), 2.21-2.10 (m, 1H).

Example 12: Synthesis of5-[[4-chloro-2-[[(2-hydroxy-2-methyl-propyl)amino]methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added 1-amino-2-methyl-propan-2-ol(100 mg, 0.89 mmol), AcOH (100 μL, 1.64 mmol) followed by Na(OAc)₃BH(100 mg, 0.47 mmol) and the resulting suspension was stirred at roomtemperature overnight. The reaction mixture was diluted with 2:1CHCl₃/IPA (30 mL) and washed with water (15 mL), dried (MgSO₄),concentrated in vacuo and purified by reverse phase preparative HPLC(CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-2-[[(2-hydroxy-2-methyl-propyl)amino]methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile,er: ˜3.5:1. MS: (ES) m/z calculated for C₃₃H₃₃ClN₃O₃ [M+H]⁺ 554.2, found554.5. ¹H NMR (400 MHz, Methanol-d₄) δ 8.96 (dd, J=19.1, 2.0 Hz, 2H),8.42 (dd, J=2.4, 1.8 Hz, 1H), 7.54-7.27 (m, 9H), 7.12 (s, 1H), 6.02 (dd,J=6.4, 4.2 Hz, 1H), 5.40 (d, J=2.0 Hz, 2H), 4.26 (s, 2H), 3.27-3.14 (m,1H), 3.04-2.89 (m, 3H), 2.63-2.49 (m, 1H), 2.15 (ddt, J=13.4, 8.8, 4.8Hz, 1H), 1.24 (d, J=8.6 Hz, 6H).

Example 13: Synthesis of5-[[4-chloro-2-[[(5-oxopyrrolidin-2-yl)methylamino]methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added5-(aminomethyl)pyrrolidin-2-one (100 mg, 0.877 mmol), AcOH (100 μL, 1.66mmol) followed by Na(OAc)₃BH (100 mg, 0.47 mmol) and the resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/IPA (30 mL) and washed with water (15mL), dried (MgSO₄), concentrated in vacuo and purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-2-[[(5-oxopyrrolidin-2-yl)methylamino]methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile,er: ˜3.5:1. MS: (ES) m/z calculated for C₃₄H₃₂ClN₄O₃ [M+H]⁺ 579.2, found579.5. ¹H NMR (400 MHz, Methanol-d₄) δ 8.97 (dd, J=18.3, 2.0 Hz, 2H),8.39 (td, J=2.1, 0.7 Hz, 1H), 7.54 (d, J=0.6 Hz, 1H), 7.50-7.23 (m, 8H),7.12 (s, 1H), 6.05-5.97 (m, 1H), 5.48-5.35 (m, 2H), 4.36-4.20 (m, 2H),3.99 (p, J=6.3 Hz, 1H), 3.29-3.11 (m, 3H), 3.04-2.92 (m, 1H), 2.61-2.48(m, 1H), 2.47-2.26 (m, 3H), 2.13 (ddt, J=13.2, 8.9, 4.8 Hz, 1H),1.92-1.76 (m, 1H).

Example 14: Synthesis of5-[[4-chloro-5-[(1S)-4-phenylindan-1-yl]oxy-2-[(1H-pyrazol-5-ylmethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was added 1H-pyrazol-5-ylmethanaminehydrochloride (100 mg, 0.75 mmol), Et₃N (100 μL, 0.723 mmol), AcOH (100μL, 1.66 mmol) followed by Na(OAc)₃BH (100 mg, 0.47 mmol) and theresulting suspension was stirred at room temperature overnight. Thereaction mixture was diluted with 2:1 CHCl₃/IPA (30 mL) and washed withwater (15 mL), dried (MgSO₄), concentrated in vacuo and purified byreverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain5-[[4-chloro-5-[(1S)-4-phenylindan-1-yl]oxy-2-[(1H-pyrazol-5-ylmethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile,er: ˜3.5:1. MS: (ES) m/z calculated for C₃₃H₂₉ClN₅O₂ [M+H]⁺ 562.2, found562.5. ¹H NMR (400 MHz, Methanol-d₄) δ 8.93 (dd, J=8.2, 2.1 Hz, 2H),8.33 (t, J=2.1 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.52-7.26 (m, 9H), 7.10(s, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.01 (dd, J=6.5, 4.2 Hz, 1H), 5.42-5.30(m, 2H), 4.25 (d, J=10.5 Hz, 4H), 3.34-3.14 (m, 1H), 2.98 (ddd, J=16.2,8.2, 5.3 Hz, 1H), 2.55 (ddt, J=13.9, 8.2, 6.1 Hz, 1H), 2.14 (ddt,J=13.3, 8.5, 5.0 Hz, 1H).

Example 15: Synthesis of3-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-2,2-dimethyl-propanoicacid

To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.104 mmol) in DMF (2 mL) was 3-amino-2,2-dimethyl-propanoicacid hydrochloride (100 mg, 0.653 mmol), Et₃N (100 μL, 0.723 mmol), AcOH(100 μL, 1.66 mmol) followed by Na(OAc)₃BH (100 mg, 0.47 mmol) and theresulting suspension was stirred at room temperature overnight. Thereaction mixture was diluted with 2:1 CHCl₃/IPA (30 mL) and washed withwater (15 mL), dried (MgSO₄), concentrated in vacuo and purified byreverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain3-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-2,2-dimethyl-propanoicacid, er: ˜3.5:1. MS: (ES) m/z calculated for C₃₄H₃₃CN₃O₄ [M+H]582.2,found 582.5. ¹H NMR (400 MHz, Methanol-d₄) δ 9.02 (d, J=2.1 Hz, 1H),8.93 (d, J=2.0 Hz, 1H), 8.44 (s, 1H), 7.51 (s, 1H), 7.45 (d, J=2.0 Hz,7H), 7.31 (s, 1H), 7.11 (s, 1H), 6.01 (dd, J=6.5, 4.2 Hz, 1H), 5.43 (d,J=2.2 Hz, 2H), 4.26 (s, 2H), 3.09 (d, J=15.0 Hz, 3H), 3.04-2.90 (m, 1H),2.62-2.45 (m, 1H), 2.24-2.05 (m, 1H), 1.28 (d, J=7.9 Hz, 6H).

Example 16: Synthesis of(5-[[4-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile

Step a: To a 500 mL three-neck round bottom flask equipped with aninternal thermometer under nitrogen was added(S)-(−)-2-methyl-CBS-oxazaborolidine (7.1 mL, 7.1 mmol, 1M THF) andborane-dimethyl sulfide (3.6 mL, 7.2 mmol, 2M THF) at room temperature.The mixture was stirred for 10 min then diluted with dichloromethane (60mL). Borane-dimethyl sulfide (130 mL, 260 mmol, 2M THF) was added atroom temperature and the mixture was cooled to −30° C. A solution of4-bromoindan-1-one (13.6 g, 64.4 mmol) in dichloromethane (40 mL) wasadded slowly over 25 min while maintaining the internal temperaturebetween −30° C. and −20° C. After 1 h, the reaction was quenchedcarefully by the dropwise addition of methanol (50 mL). The solvent wasremoved in vacuo and the crude solid was purified by flashchromatography (15% EtOAc in hexane). The resulting pure(R)-4-bromoindan-1-ol was recrystallized from 1:5 EtOAc/hexane (100 mL)to give the product with 99.2% ee. Enantiomeric excess was determined byintegration of peaks that were separated on a RegisCell 250×4.6 mmcolumn at a flow rate of 1.2 mL/min and an isochratic mobile phase of 5%isopropanol in hexane. MS: (ES) m/z calculated for C₉H₉BrO [M-OH]⁺197.0, found 197.2. Chiral HPLC: 7(R)-4-bromoindan-1-ol was eluted using5% IPA in hexane: t_(R)=7.63 min.

Step b: To a cooled (0° C.) solution of (R)-4-bromoindan-1-ol (11.2 g,52.6 mmol), 5-chloro-2,4-dihydroxy-benzaldehyde (9.1 g, 52.6 mmol), andtriphenylphosphine (13.8 g, 52.6 mmol) in THE (100 mL) was slowly addeddiisopropyl azodicarboxylate (10.3 mL, 52.6 mmol) in THE (25 mL). Themixture was allowed to gradually warm to room temperature for threedays. The volatiles were removed in vacuo and the resulting cruderesidue was purified by flash chromatography (20% EtOAc in hexane) toafford 4-[(1S)-4-bromoindan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde.Approximately 22% of racemization was observed during the reaction andthe enantiomerica ratio of the obtained product was ˜3.5:1. Enantiomericratio was determined by integration of peaks that were separated on aRegisCell 250×4.6 mm column at a flow rate of 1 mL/min and an isochraticmobile phase of 50% isopropanol in hexane (desired enantiomer t_(R)=6.68min, undesired enantiomer t_(R)=5.45 min). All of the final compoundsdescribed in examples 17 to 36 were prepared using this intermediatewith er: 3.5:1. MS: (ES) m/z calculated for C₁₆H₁₂BrClO₃ [M−H]⁻ 365.0,found 365.1.

Step c: To a solution of4-[(1S)-4-bromoindan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde (2.0 g,5.4 mmol) in DMF (12 mL) was added (5-cyano-3-pyridyl)methylmethanesulfonate (1.5 g, 7.1 mmol), followed by Cs₂CO₃ (3.5 g, 11 mmol).The resulting suspension was stirred at 75° C. for 2 h. After cooling toroom temperature, the reaction mixture was diluted with EtOAc (50 mL)and washed with water (20 mL). The aqueous layer was re-extracted withEtOAc (2×25 mL). The combined organic layers were dried (MgSO₄),filtered, and concentrated in vacuo. The crude was purified by flashchromatography (SiO₂, 50% EtOAc in hexanes) to obtain5-[[5-[(1S)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₃H₁₆BrCN₂O₃ [M+H]⁺ 483.0, found 483.2.

Step d: To a solution of5-[[5-[(1)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(0.83 g, 1.7 mmol) in 1,2-dimethoxyethane (10 mL) was addedphenylboronic acid (0.22 g, 1.8 mmol), aqueous 2M K₂CO₃ (1.3 mL, 2.6mmol) and the resulting mixture was bubbled with nitrogen gas for a fewminutes. Tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.086 mmol)was then added and the reaction mixture was stirred at 80° C. overnight.After cooling to room temperature, the reaction mixture was diluted withEtOAc (30 mL) and washed with water (30 mL) and brine (30 mL). Theorganic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude product was purified by flash chromatography (SiO₂, 30% EtOAcin hexanes) to obtain5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₉H₂₁CN₂O₃ [M+H]⁺ 481.1, found 481.4.

Step e: To a solution of5-[[4-chloro-2-formyl-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(150 mg, 0.31 mmol) in DMF (3 mL) was added azetidin-3-ol hydrochloride(130 mg, 1.2 mmol), triethylamine (0.40 mL, 2.9 mmol), acetic acid (0.20mL, 2.9 mmol), and sodium triacetoxyborohydride (190 mg, 0.88 mmol).After stirring at room temperature overnight, the reaction mixture wasdiluted with 2:1 CHCl₃/i-PrOH (30 mL) and washed with water (15 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The crude residue was purified by reverse phase preparative HPLC(CH₃CN—H₂O with 0.1% TFA) to obtain(5-[[4-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]-5-[(1S)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrileas a di-trifluoroacetic acid salt. The diastereomeric ratio of the finalcompound is assumed to be ˜3:1 based on the enantiomeric ration of theintermediate used in step b., er: ˜3.5:1. MS: (ES) m/z calculated forC₃₂H₂₉ClN₃O₃ [M+H]⁺ 538.2, found 538.5. ¹H NMR (400 MHz, Methanol-d) δ8.98 (s, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.42 (s, 1H), 7.51 (s, 1H),7.49-7.40 (m, 4H), 7.40-7.33 (m, 2H), 7.33-7.28 (m, 2H), 7.11 (d, J=8.5Hz, 1H), 6.01 (t, J=5.4 Hz, 1H), 5.42 (s, 2H), 4.56 (m, 1H), 4.43 (s,2H), 4.40-4.28 (m, 2H), 4.06-3.88 (m, 2H), 3.21-3.13 (m, 1H), 3.04-2.88(m, 1H), 2.55 (m, 1H), 2.13 (m, 1H).

Example 17: Synthesis of(2S,3R)-2-[[5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-(pyridazin-3-ylmethoxy)phenyl]methylamino]-3-hydroxy-butanoicacid

Step a: To a cold (0° C.) solution of pyridazin-3-ylmethanol (500 mg,4.5 mmol) and triethylamine (1.26 mL, 9.1 mmol) in CH₂Cl₂ (5 mL) wasadded methanesulfonyl chloride (0.60 mL, 7.8 mmol) by dropwise addition.The resulting mixture was allowed to warm to room temperature andstirred for 1 h. The reaction mixture was added to water and the organicphase was separated. The aqueous phase was extracted with EtOAc, andsolvent was removed from the combined organic layers in vacuo. The cruderesidue was purified by flash chromatography (SiO₂, 50% EtOAc inhexanes) to obtain (2-chloropyrimidin-5-yl)methyl methanesulfonate.

Step b: To a solution of5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-hydroxy-benzaldehyde(150 mg, 0.393 mmol) and pyridazin-3-ylmethyl methanesulfonate (111 mg,0.56 mmol) in DMF (3 mL) was added cesium carbonate (255 mg, 0.8 mmol).The mixture was stirred at 70° C. overnight. Solvent was removed invacuo, and the crude residue was purified by flash chromatography toobtain5-chloro-2-[(2-chloropyrimidin-5-yl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-benzaldehyde.MS: (ES) m/z calculated for C₂₇H₂₁ClFN₂O₃ [M+H]⁺ 475.1, found 475.2.

Step c: To a solution of5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-(pyridazin-3-ylmethoxy)benzaldehyde(50 mg, 0.1 mmol) in DMF (3 mL) was added(2S,3R)-2-amino-3-hydroxy-butanoic acid (100 mg, 0.57 mmol) Na(OAc)₃BH(100 mg, 0.49 mmol) and acetic acid (0.10 mL, 1.8 mmol). The resultingsuspension was stirred at 45° C. for overnight. The reaction mixture wasdiluted with 2:1 CHCl₃/i-PrOH (5 mL), washed with water (1 mL), andconcentrated in vacuo. The crude residue was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA). The fractions were combinedand diluted with 2:1 CHCl₃/i-PrOH (30 mL). The organic layer was washedwith saturated aqueous NaHCO₃ (15 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to obtain(2S,3R)-2-[[2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]acetyl]amino]-3-hydroxy-butanoicacid, dr: ˜3.5:1. MS: (ES) m/z calculated for C₃₁H₃₀ClFN₃O₅ [M+H]578.2,found 578.3. ¹H NMR (400 MHz, Methanol-d₄) δ. ¹H NMR (400 MHz,Methanol-d₄) δ 8.87 (d, J=1.4 Hz, 1H), 8.66 (ddd, J=2.5, 1.5, 0.7 Hz,1H), 8.59 (d, J=2.6 Hz, 1H), 7.48-7.14 (m, 8H), 7.10 (d, J=1.5 Hz, 1H),5.94 (dd, J=6.4, 4.3 Hz, 1H), 5.60-5.45 (m, 2H), 4.24 (s, 2H), 3.99 (p,J=6.5 Hz, 1H), 3.32-3.14 (m, 1H), 3.07-2.94 (m, 1H), 2.87-2.75 (m, 1H),2.52 (dq, J=13.8, 6.6 Hz, 1H), 2.07 (ddq, J=13.3, 8.9, 5.0, 4.6 Hz, 1H),1.35-1.25 (m, 3H).

Example 18: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-2-methyl-propanoicacid

To a solution of5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.1 mmol) in DMF (3 mL) was added(2S)-2-amino-3-hydroxy-2-methyl-propanoic acid (100 mg, 0.84 mmol)Na(OAc)₃BH (100 mg, 0.49 mmol) and acetic acid (0.10 mL, 1.8 mmol). Theresulting suspension was stirred at 45° C. for overnight. The reactionmixture was diluted with 2:1 CHCl₃/i-PrOH (5 mL), washed with water (1mL), and concentrated in vacuo. The crude residue was purified byreverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA). The fractionswere combined and diluted with 2:1 CHCl₃/i-PrOH (30 mL). The organiclayer was washed with saturated aqueous NaHCO₃ (15 mL), dried (MgSO₄),filtered, and concentrated in vacuo to obtain obtain(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-2-methyl-propanoicacid, dr: ˜3.5:1. MS: (ES) m/z calculated for C₃₃H₃₀ClFN₃O₅ [M+H]⁺602.2, found 602.1. ¹H NMR (400 MHz, Methanol-d₄) S. ¹H NMR (400 MHz,Methanol-d₄) δ 8.99 (d, J=2.1 Hz, 1H), 8.89 (d, J=1.9 Hz, 1H), 8.44 (dt,J=9.6, 2.0 Hz, 1H), 7.55 (s, 1H), 7.49-7.14 (m, 7H), 7.06 (s, 1H), 6.00(dd, J=6.6, 4.4 Hz, 1H), 5.45-5.32 (m, 2H), 4.22 (s, 2H), 3.92 (d,J=11.9 Hz, 1H), 3.73 (d, J=12.0 Hz, 1H), 3.02 (ddd, J=16.2, 8.4, 5.4 Hz,1H), 2.82 (ddd, J=16.2, 8.2, 5.5 Hz, 1H), 2.61-2.43 (m, 1H), 2.18-2.05(m, 1H), 1.44 (s, 3H).

Example 19: Synthesis of 1-methylethyl(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoate

To a solution of5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(67 mg, 0.13 mmol) in NMP (1 mL) was added L-serine isopropyl esterhydrochloride (110 mg, 0.59 mmol, prepared according to the procedure inJ. Med. Chem. 53(19), 6625-6837; 2010),N-ethyl-N-(propan-2-yl))propan-2-amine (0.09 mL, 0.50 mmol), Na(OAc)₃BH(100 mg, 0.49 mmol) and acetic acid (0.10 mL, 1.8 mmol). The resultingsuspension was stirred at 50° C. for 20 minutes. The reaction mixturewas diluted with 2:1 CHCl₃/i-PrOH (5 mL), washed with water (1 mL), andconcentrated in vacuo. The crude residue was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain 1-methylethyl(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoateas a trifluoroacetic acid salt. The salt was neutralized by passing thepurified fractions through an Agilent Technologies PL-HCO3 MP SPEcartridge to obtain the neutral form. dr: ˜3.5:1. MS: (ES) m/zcalculated for C₃₅H₃₃ClFN₃O₅ [M+H]⁺ 630.2, found 630.2. ¹H NMR (400 MHz,Methanol-d) δ 8.97 (d, J=2.2 Hz 1H), 8.92 (d, J=2.0 Hz, 1H), 8.51 (s,1H), 7.47 (s, 1H), 7.45-7.17 (m, 7H), 7.08 (s, 1H), 6.04-5.99 (m, 1H),5.37 (s, 2H), 5.06 (m, 1H), 4.24-4.13 (m, 2H), 3.97-3.85 (m, 3H),3.09-2.98 (m, 1H), 2.88-2.78 (m, 1H), 2.62-2.53 (m, 1H), 2.20-2.10 (m,1H), 1.29-1.22 (m, 6H).

Example 20: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1R,2R)-2-fluoro-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of 4-bromoindan-1-one (10 g, 47 mmol) dissolved inmethanol (110 mL) was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor™, 25 g, 71 mmol) and 98% sulfuricacid (0.25 mL), After the mixture was stirred for 17 h at 50° C., it wasfiltered to remove the white solid. The solvent was removed from thefiltrate in vacuo and the crude solid was purified by flashchromatography (6% MTBE in hexane) to obtain2-fluoro-4-bromoindan-1-one. MS: (ES) m/z calculated for C₉H₇BrFO [M+H]⁺279.0, found 279.2.

Step b: To a solution of 4-bromo-2-fluoroindan-1-one (2.0 g, 8.7 mmol)in ethanol (40 mL) was added sodium borohydride (380 mg, 10 mmol). Themixture was stirred for 10 minutes at room temperature, then quenchedwith the addition of saturated aqueous sodium bicarbonate (10 mL).Ethanol was removed in vacuo, and the residue was extracted with ethylacetate, washed with brine, dried over sodium sulfate, filtered andconcentrated. The crude solid was purified by flash chromatography toobtain 4-bromo-2-fluoroindan-1-ol. MS: (ES) m/z calculated for C₉H₇BrF[M-OH]⁺ 213.0, found 213.0. The product was arbitrarily assigned thetrans configuration, rel-(1R,2R)-4-bromo-2-fluoroindan-1-ol.

Step c: To a cooled (0° C.) solution ofrel-(1R,2R)-4-bromo-2-fluoroindan-1-ol (1.2 g, 5.3 mmol),5-chloro-2,4-dihydroxybenzaldehyde (0.96 g, 5.6 mmol), andtriphenylphosphine (1.5 g, 5.7 mmol) in THF (40 mL) was slowly addedDIAD (1.2 g, 5.6 mmol) in THE (40 mL). The mixture was allowed to warmto room temperature and stirred for 16 h. The volatiles were removed invacuo and the resulting crude residue was purified by flashchromatography (20% EtOAc in hexane) to afford4-[rel-(1R,2R)-4-bromo-2-fluoro-indan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde.¹H NMR (400 MHz, DMSO-d) δ 11.25 (s, 1H), 10.10 (s, 1H), 7.71 (s, 1H),7.67 (d, J=8.8 Hz), 7.49 (d, J=8.0 Hz), 7.33 (d, J=7.6 Hz), 7.00 (s,1H), 6.20 (dd, J=16 Hz, 2.8 Hz), 5.65-5.47 (m, 1H), 3.62-3.46 (m, 1H),3.21-3.03 (m, 1H).

Step d: To a solution of4-[rel-(1R,2R)-4-bromo-2-fluoro-indan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde(340 mg, 0.87 mmol) in DMF (4 mL) was added (5-cyano-3-pyridyl)methylmethanesulfonate (300 mg, 1.4 mmol), followed by Cs₂CO₃ (1.0 g, 3.1mmol). The resulting suspension was stirred at 50° C. for 30 min. Thereaction mixture was diluted with dichloromethane and washed with water,and the organic layer was concentrated in vacuo. The crude residue waspurified by flash chromatography (SiO₂, 50% EtOAc in hexanes) to obtain5-[[5-[rel-(1R,2R)-4-bromo-2-fluoro-indan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₃H₁₆BrClFN₂O₃ [M+H]⁺ 501.0, found 501.0.

Step e: To a solution of5-[[5-[rel-(1R,2R)-4-bromo-2-fluoro-indan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(270 mg, 0.54 mmol) in DME (5 mL) was added 2-flurophenylboronic acid(120 mg, 0.86 mmol), K₂CO₃ (240 mg, 1.7 mmol) and the resulting mixturewas bubbled with nitrogen gas for a few minutes. Pd(PPh₃)₄ (110 mg,0.096 mmol) was then added and the reaction mixture was stirred at 80°C. for 2 h. After cooling to room temperature, the reaction mixture wasconcentrated in vacuo and the crude product was purified by flashchromatography (SiO₂, 30% EtOAc in hexanes) to obtain5-[[4-chloro-5-[rel-(1R,2R)-2-fluoro-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₉H₂₀ClF₂N₂O₃ [M+H]⁺ 517.1, found 517.1.

Step f: To a solution of5-[[4-chloro-5-[rel-(1R,2R)-2-fluoro-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.097 mmol) in DMF (2 mL) was added L-serine (100 mg, 0.95mmol), Na(OAc)₃BH (105 mg, 0.50 mmol) and acetic acid (0.10 mL, 1.8mmol). The resulting mixture was stirred at 50° C. for 2 h. The reactionmixture was diluted with 2:1 CHCl₃/i-PrOH (5 mL), washed with water (1mL), and concentrated in vacuo. The crude residue was purified byreverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[rel-(1R,2R)-2-fluoro-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid. To obtain the neutral form, purified HPLC fractions were basifiedwith sodium bicarbonate, and solvent was removed in vacuo. The residuewas dissolved in 2:1 CHCl₃/i-PrOH, dried over Na₂SO₄, filtered andconcentrated. The residue was finally lyophilized fromwater/acetonitrile to obtain a powder. MS: (ES) m/z calculated forC₃₂H₂₇ClF₂N₃O₅ [M+H]⁺ 606.2, found 606.2. ¹H NMR (400 MHz, Methanol-d) δ8.98 (s, 1H), 8.92 (s, 1H), 8.42 (s, 1H), 7.58 (s, 1H), 7.47-7.35 (m,5H), 7.31-7.19 (m, 3H), 6.11 (dd, J=16 Hz, 3.7 Hz, 1H), 5.50-5.30 (m,3H), 4.44-4.29 (m, 2H), 4.02 (s, 3H), 3.45-3.33 (m, 1H), 3.17-3.02 (m,1H).

Example 21: Synthesis ofN-[2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]ethyl]prop-2-enamide

To a solution of5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(54 mg, 0.11 mmol) in DMF (2 mL) was addedN-(2-aminoethyl)prop-2-enamide hydrochloride (104 mg, 0.69 mmol,prepared according to the procedure in Analytical Chemistry, 86 (5),2429-2435; 2014), N-ethyl-N-(propan-2-yl))propan-2-amine (0.12 mL, 0.69mmol), Na(OAc)₃BH (96 mg, 0.45 mmol) and acetic acid (16 mg, 0.27 mmol).The resulting suspension was stirred at room temperature for 3.5 hours.The reaction mixture was diluted with 2:1 CHCl₃/i-PrOH (5 mL), washedwith water (1 mL), and concentrated in vacuo. The crude residue waspurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtainN-[2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]ethyl]prop-2-enamideas a trifluoroacetic acid salt. The salt was neutralized by passing thepurified fractions through an Agilent Technologies PL-HCO3 MP SPEcartridge to obtain the neutral form. er: ˜3.5:1. MS: (ES) m/zcalculated for C₃₄H₃₁ClFN₄O₃ [M+H]⁺ 597.2, found 597.5. ¹H NMR (400 MHz,Methanol-d) δ 9.00 (d, J=2.3 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.42 (t,J=1.9 Hz, 1H), 7.51 (s, 1H), 7.45-7.30 (m, 5H), 7.28-7.16 (m, 2H), 7.09(s, 1H), 6.22 (s, 1H), 6.20 (d, J=1.2 Hz, 1H), 6.02 (dd, J=6.8 Hz, 4.0Hz), 5.71 (dd, J=6.4 Hz, 5.6 Hz, 1H), 5.42 (m, 2H), 3.52 (t, J=4.8 Hz,2H), 3.22 (t, J=6.0 Hz, 2H), 3.08-2.98 (m, 1H), 2.88-2.78 (m, 1H),2.60-2.50 (m, 1H), 2.17-2.07 (m, 1H).

Example 22: Synthesis of1-[[2-[(2-aminopyrimidin-5-yl)methoxy]-5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methyl]piperidin-4-ol

Step a: To a cold (0° C.) solution of (2-chloropyrimidin-5-yl)methanol(710 mg, 4.9 mmol) and triethylamine (1.8 mL, 13 mmol) in EtOAc (20 mL)was added methanesulfonyl chloride (0.60 mL, 7.8 mmol) by dropwiseaddition. The resulting mixture was allowed to warm to room temperatureand stirred for 2 days. The reaction mixture was added to water and theorganic phase was separated. The aqueous phase was extracted with EtOAc,and solvent was removed from the combined organic layers in vacuo. Thecrude residue was purified by flash chromatography (SiO₂, 50% EtOAc inhexanes) to obtain (2-chloropyrimidin-5-yl)methyl methanesulfonate. MS:(ES) m/z calculated for C₆H₈ClN₂O₃S [M+H]⁺ 223.0, found 223.0.

Step b: To a solution of5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-hydroxy-benzaldehyde(200 mg, 0.52 mmol) and (2-chloropyrimidin-5-yl)methyl methanesulfonate(200 mg, 0.90 mmol) in DMF (2 mL) was added cesium carbonate (400 mg,1.2 mmol). The mixture was stirred at 40° C. overnight. Solvent wasremoved in vacuo, and the crude residue was purified by flashchromatography to obtain5-chloro-2-[(2-chloropyrimidin-5-yl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-benzaldehyde.MS: (ES) m/z calculated for C₂₇H₂₀Cl₂FN₂O₃ [M+H]⁺ 509.1, found 509.2.

Step c: To a solution of5-chloro-2-[(2-chloropyrimidin-5-yl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-benzaldehyde(50 mg, 0.098 mmol) in THE (1 mL) in a 4 mL glass vial was added 7Mammonia in methanol (1.4 mL, 9.8 mmol). The vial was secured with ateflon-lined screwcap and placed in an aluminum heating block maintainedat 100° C. for four hours. Solvent was removed from the reaction mixtureand the crude residue of2-[(2-aminopyrimidin-5-yl)methoxy]-5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-benzaldehydewas used without purification. MS: (ES) m/z calculated for C₂₇H₂₂ClFN₂O₃[M+H]⁺ 490.1, found 490.2.

Step d: To a solution of crude2-[(2-aminopyrimidin-5-yl)methoxy]-5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-benzaldehyde(50 mg, 0.1 mmol) in NMP (1 mL) was added 4-hydroxypiperidine (113 mg,1.1 mmol), Na(OAc)₃BH (125 mg, 0.59 mmol), and acetic acid (0.075 mL,1.3 mmol). The mixture was stirred at room temperature overnightfollowed by an additional 6 h at 50° C. The resulting suspension wasstirred at room temperature for 3.5 hours. The reaction mixture wasdiluted with 2:1 CHCl₃/i-PrOH (5 mL), washed with water (1 mL), andconcentrated in vacuo. The crude residue was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA) to obtain1-[[2-[(2-aminopyrimidin-5-yl)methoxy]-5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methyl]piperidin-4-olas a trifluoroacetic acid salt. The salt was neutralized by passing thepurified fractions through an Agilent Technologies PL-HCO3 MP SPEcartridge to obtain the neutral form. er: ˜3.5:1. MS: (ES) m/zcalculated for C₃₂H₃₃ClFN₄O₃ [M+H]⁺ 575.2, found 575.4. ¹H NMR (400 MHz,Methanol-d) δ 8.45 (d, J=2.9 Hz, 2H), 7.52 (d, J=4.8 Hz, 1H), 7.45-7.14(m, 7H), 6.07 (dd, J=6.8 Hz, 4.8 Hz, 1H), 5.14-5.10 (m, 2H), 4.23 (d,J=5.6 Hz, 2H), 3.53-3.43 (m, 1H), 3.10-3.00 (m, 2H), 2.91-2.79 (m, 1H),2.70-2.58 (m, 1H), 2.21-2.06 (m, 2H), 1.94-1.84 (m, 2H), 1.70-1.60 (m,1H).

Example 23: Synthesis of5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-[(4-hydroxy-1-piperidyl)methyl]phenoxy]methyl]pyridine-3-carbonitrile

To a solution of5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(170 mg, 0.34 mmol) in NMP (2 mL) was added 4-hydroxypiperidine (256 mg,2.5 mmol), Na(OAc)₃BH (253 mg, 1.2 mmol) and acetic acid (0.040 mL, 0.7mmol). The resulting suspension was stirred for 1 day at roomtemperature. The reaction mixture was diluted with 2:1 CHCl₃/i-PrOH (12mL), washed with water (4 mL), and concentrated in vacuo. The cruderesidue was purified by reverse phase preparative HPLC (CH₃CN—H₂O with0.1% TFA) to obtain5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-[(4-hydroxy-1-piperidyl)methyl]phenoxy]methyl]pyridine-3-carbonitrile,er: ˜3.5:1. MS: (ES) m/z calculated for C₃₄H₃₂ClFN₃O₃ [M+H]⁺ 584.2,found 584.4. ¹H NMR (400 MHz, Methanol-d) δ 8.90 (s, 1H), 8.87 (m, 1H),8.31 (m, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.39-7.22 (m, 5H), 7.21-7.09 (m,2H), 7.05 (d, J=2.2 Hz, 1H), 6.00-5.96 (m, 1H), 5.32 (m, 2H), 4.23 (d,J=6.0 Hz, 2H), 3.47-3.38 (m, 1H), 3.06-2.91 (m, 2H), 2.82-2.71 (m, 1H),2.56-2.46 (m, 1H), 2.11-1.99 (m, 2H), 1.87-1.80 (m, 2H), 1.66-1.52 (m,1H).

Example 24: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of5-[[5-[(1S)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(570 mg, 1.2 mmol) in 1,2-dimethoxyethane (10 mL) was added2-fluorophenylboronic acid (250 mg, 1.8 mmol), aqueous 2M K₂CO₃ (1.20mL, 3.5 mmol) and the resulting mixture was bubbled with nitrogen gasfor a few minutes. Tetrakis(triphenylphosphine)palladium(0) (140 mg,0.12 mmol) was then added and the reaction mixture was stirred at 80° C.for 2 h. After cooling to room temperature, the reaction mixture wasdiluted with EtOAc (30 mL) and washed with water (30 mL) and brine (30mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated invacuo. The crude product was purified by flash chromatography (SiO₂, 40%EtOAc in hexanes) to obtain5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₉H₂₀ClFN₂O₃ [M+H]⁺ 499.1, found 499.1.

Step b: To a solution of5-[[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(50 mg, 0.10 mmol) in DMF (3 mL) was added L-serine (100 mg, 0.95 mmol)and sodium triacetoxyborohydride (150 mg, 0.71 mmol). The resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/i-PrOH (30 mL), washed with water (15mL), dried (MgSO₄), and concentrated in vacuo. The crude residue waspurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtain(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid as a di-trifluoroacetic acid salt, dr: ˜3.5:1. MS: (ES) m/zcalculated for C₃₂H₂₇ClFN₃O₅ [M+H]⁺ 588.2, found 588.4. ¹H NMR (400 MHz,Methanol-d) δ 8.99 (d, J=2.1 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.43 (s,1H), 7.53 (s, 1H), 7.45-7.31 (m, 4H), 7.30-7.15 (m, 3H), 7.11 (s, 1H),6.08-5.99 (m, 1H), 5.38 (s, 2H), 4.38 (d, J=13.4 Hz, 1H), 4.31 (d,J=13.1 Hz, 1H), 4.03-3.99 (m, 3H), 3.11-2.98 (m, 1H), 2.90-2.76 (m, 1H),2.63-2.50 (m, 1H), 2.20-2.09 (m, 1H).

Example 25: Synthesis of(2S)-2-[[5-chloro-2-methoxy-4-[(1S)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of4-[(1S)-4-bromoindan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde (200 mg,0.54 mmol) in DMF (1 mL) was added iodomethane (130 μL, 2.1 mmol),followed by Cs₂CO₃ (360 mg, 1.1 mmol). The resulting suspension wasstirred at 40° C. for 1 h. After cooling to room temperature, thereaction was diluted with dichloromethane (15 mL) and washed with water(20 mL). The aqueous layer was re-extracted with dichloromethane (2×20mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo to obtain4-[(1S)-4-bromoindan-1-yl]oxy-5-chloro-2-methoxy-benzaldehyde. MS: (ES)m/z calculated for Cl₇H₁₄BrClO₃ [M+Na]⁺ 403.0, found 403.2.

Step b: To a solution of4-[(1S)-4-bromoindan-1-yl]oxy-5-chloro-2-methoxy-benzaldehyde (210 mg,0.54 mmol) in DME (5 mL) was added phenylboronic acid (79 mg, 0.65mmol), aqueous 2M K₂CO₃ (0.41 mL, 0.81 mmol) and the resulting mixturewas bubbled with nitrogen gas for a few minutes.Tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.81 mmol) was thenadded and the reaction mixture was stirred at 80° C. overnight. Aftercooling to room temperature, the reaction mixture was diluted with EtOAc(10 mL) and washed with water (15 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude product waspurified by flash chromatography (SiO₂, 20% EtOAc in hexanes) to obtain5-chloro-2-methoxy-4-[(1S)-4-phenylindan-1-yl]oxy-benzaldehyde. MS: (ES)m/z calculated for C₂₃H₁₉ClO₃ [M+Na]⁺ 401.1, found 401.3.

Step c: To a solution of5-chloro-2-methoxy-4-[(1S)-4-phenylindan-1-yl]oxy-benzaldehyde (100 mg,0.26 mmol) in DMF (3 mL) was added L-serine (100 mg, 0.95 mmol) andsodium triacetoxyborohydride (150 mg, 0.71 mmol). The resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/i-PrOH (30 mL), washed with water (15mL), dried (MgSO₄), filtered, and concentrated in vacuo. The cruderesidue was purified by reverse phase preparative HPLC (CH₃CN—H₂O with0.1% TFA) to obtain(2S)-2-[[5-chloro-2-methoxy-4-[(1S)-4-phenylindan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid as a di-trifluoroacetic acid salt, dr: ˜3.5:1. MS: (ES) m/zcalculated for C₂₆H₂₆ClNO₆ [M+Na]⁺ 490.1, found 490.3. ¹H NMR (400 MHz,Methanol-d₄) δ 7.48-7.37 (m, 6H), 7.37-7.30 (m, 3H), 7.00 (s, 1H), 6.01(dd, J=6.4, 4.2 Hz, 1H), 4.33 (d, J=13.1 Hz, 1H), 4.23 (d, J=13.2 Hz,1H), 4.04-3.98 (m, 2H), 3.96 (s, 3H), 3.93 (t, J=4.2 Hz, 1H), 3.26-3.15(m, 1H), 2.98 (ddd, J=16.2, 8.2, 5.4 Hz, 1H), 2.59 (ddt, J=13.9, 8.1,6.0 Hz, 1H), 2.24-2.10 (m, 1H).

Example 26: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluoro-3-methoxy-phenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluoro-3-methoxy-phenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid was performed in an analogous route to Example 24, substituting2-fluoro-3-methoxyphenylboronic acid for 2-fluorophenylboronic acid inStep a. dr: ˜3.5:1. MS: (ES) m/z calculated for C₃₃H₂₉ClFN₃O₆ [M+H]⁺618.2, found 618.4. ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J=2.1 Hz,1H), 8.92 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 7.53 (s, 1H), 7.35 (dd,J=19.5, 7.3 Hz, 2H), 7.30 (s, 1H), 7.23-7.04 (m, 3H), 6.89 (t, J=7.1 Hz,1H), 6.07-5.98 (m, 1H), 5.37 (d, J=2.7 Hz, 2H), 4.38 (d, J=13.1 Hz, 1H),4.31 (d, J=13.1 Hz, 1H), 4.01 (s, 3H), 3.91 (d, J=0.6 Hz, 2H), 3.07-2.97(m, 1H), 2.89-2.78 (m, 1H), 2.65-2.53 (m, 1H).

Example 27: Synthesis of(2S)-2-[[5-chloro-2-ethoxy-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Synthesis of(2S)-2-[[5-chloro-2-ethoxy-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid was performed in an analogous route to Example 25, substitutingiodoethane for iodomethane in Step a and 2-fluorophenylboronic acid forphenylboronic acid in Step b. dr: ˜3.5:1. MS: (ES) m/z calculated forC₂₇H₂₇ClFNO₅ [M+Na]⁺ 522.2, found 522.4. ¹H NMR (400 MHz, DMSO-d₆) δ7.51-7.39 (m, 4H), 7.36 (t, J=7.5 Hz, 1H), 7.34-7.27 (m, 3H), 7.01 (s,1H), 6.10-6.02 (m, 1H), 4.14 (q, J=6.9 Hz, 2H), 3.94 (s, 2H), 3.72 (dd,J=11.2, 4.5 Hz, 1H), 3.62 (dd, J=11.2, 6.5 Hz, 1H), 3.31 (r s, 1H),3.22-3.09 (m, 1H), 3.00-2.83 (m, 1H), 2.83-2.66 (m, 1H), 2.57 (dt,J=13.5, 6.6 Hz, 1H), 2.07-1.93 (m, 1H), 1.37 (t, J=6.9 Hz, 3H).

Example 28: Synthesis of(2S)-2-[[5-chloro-2-(cyclopropylmethoxy)-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Synthesis of(2S)-2-[[5-chloro-2-(cyclopropylmethoxy)-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid was performed in an analogous route to Example 25, substitutingcyclopropylmethyl bromide for iodomethane in Step a and2-fluorophenylboronic acid for phenylboronic acid in Step b. dr: ˜3.5:1.MS: (ES) m/z calculated for C₂₉H₂₉ClFNO₅ [M+Na]⁺ 548.2, found 548.4. ¹HNMR (400 MHz, Methanol-d₄) δ 7.45 (s, 1H), 7.44-7.37 (m, 2H), 7.37-7.32(m, 1H), 7.32-7.25 (m, 2H), 7.21 (dd, J=17.8, 8.2 Hz, 2H), 6.96 (d,J=14.8 Hz, 1H), 6.06-5.94 (m, 1H), 4.36 (d, J=13.9 Hz, 1H), 4.31-4.25(m, 1H), 4.08-3.88 (m, 4H), 3.08-2.99 (m, 1H), 2.87-2.75 (m, 1H),2.67-2.50 (m, 2H), 2.24-2.11 (m, 1H), 1.39-1.26 (m, 1H), 0.75-0.60 (m,2H), 0.45-0.40 (m, 2H).

Example 29: Synthesis of(2S)-2-[[5-chloro-4-[(1S)-4-(2-fluoro-3-methoxy-phenyl)indan-1-yl]oxy-2-methoxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Synthesis of(2S)-2-[[5-chloro-4-[(1S)-4-(2-fluoro-3-methoxy-phenyl)indan-1-yl]oxy-2-methoxy-phenyl]methylamino]-3-hydroxy-propanoicacid was performed in an analogous route to Example 25, substituting2-fluoro-3-methoxyphenylboronic acid for phenylboronic acid in Step b.dr: ˜3.5:1. MS: (ES) m/z calculated for C₂₇H₂₇ClFNO₆ [M+H]⁺ 516.2, found516.4. ¹H NMR (400 MHz, Methanol-d₄) δ 7.44 (s, 1H), 7.43 (d, J=6.9 Hz,1H), 7.35-7.26 (m, 2H), 7.20-7.15 (m, 1H), 7.12 (td, J=8.0, 1.9 Hz, 1H),6.98 (s, 1H), 6.89 (ddd, J=8.0, 6.3, 1.9 Hz, 1H), 6.03 (dd, J=6.5, 4.3Hz, 1H), 4.33 (d, J=13.1 Hz, 1H), 4.23 (d, J=13.1 Hz, 1H), 4.06-3.98 (m,2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.90 (d, J=4.2 Hz, 1H), 3.09-2.97 (m,1H), 2.89-2.77 (m, 1H), 2.61 (dq, J=13.7, 6.3 Hz, 1H), 2.17 (ddt,J=13.3, 9.1, 5.0 Hz, 1H).

Example 30: Synthesis of(2S)-2-[[5-chloro-4-[(1S)-4-(2-chloro-3-methoxy-phenyl)indan-1-yl]oxy-2-[(5-cyano-3-pyridyl)methoxy]phenyl]methylamino]-3-hydroxy-propanoicacid

Synthesis of(2S)-2-[[5-chloro-4-[(1S)-4-(2-chloro-3-methoxy-phenyl)indan-1-yl]oxy-2-[(5-cyano-3-pyridyl)methoxy]phenyl]methylamino]-3-hydroxy-propanoicacid was performed in an analogous route to Example 24, substituting2-chloro-3-methoxyphenylboronic acid for 2-fluorophenylboronic acid inStep a. dr: ˜3.5:1. MS: (ES) m/z calculated for C₃₃H₂₉Cl₂N₃O₆ [M+H]⁺634.2, found 634.4. ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (s, 1H), 8.92(d, J=2.0 Hz, 1H), 8.43 (s, 1H), 7.53 (s, 1H), 7.40-7.27 (m, 2H), 7.18(d, J=7.4 Hz, 1H), 7.15-7.07 (dd, J=8.3, 1.4 Hz, 3H), 6.89 (s, 1H), 6.02(d, J=14.3 Hz, 1H), 5.38 (s, 2H), 4.38 (d, J=13.2 Hz, 1H), 4.35-4.24 (m,1H), 4.01 (d, J=0.9 Hz, 3H), 3.93 (s, 3H), 3.06-2.90 m, 2H), 2.90-2.76(m, 1H), 2.68-2.49 (m, 2H), 2.19-2.02 (m, 1H).

Example 31: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of 3-fluorocatechol (5.30 g, 41.2 mmol) and K₂CO₃(17.1 g, 124 mmol) in DMF (50 mL) was added 1,2-dibromoethane (3.90 mL,45.3 mmol) and the mixture was left to stir at room temperature for 4days. Water (50 mL) was added and the mixture was extracted with EtOAc(3×50 mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 20% EtOAc in hexanes) to obtain5-fluoro-2,3-dihydro-1,4-benzodioxine. ¹H NMR (400 MHz, Chloroform-d) δ6.78-6.71 (m, 1H), 6.71-6.64 (m, 2H), 4.40-4.24 (m, 4H).

Step b: To a cooled (0° C.) solution of5-fluoro-2,3-dihydro-1,4-benzodioxine (1.0 g, 6.5 mmol) in methanol (25mL) was added bromine (1.2 g, 0.40 mL, 7.8 mmol), and the resultingmixture was allowed to warm to room temperature. After stirring for 24h, saturated aqueous sodium metabisulfite (100 mL) was added and thesolution was extracted with dichloromethane (3×25 mL). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated in vacuo.The crude product was purified by flash chromatography (SiO₂, 20% EtOAcin hexanes) to obtain 6-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine. ¹HNMR (400 MHz, Chloroform-d) δ 6.96 (ddt, J=9.0, 7.0, 0.5 Hz, 1H), 6.59(ddt, J=9.0, 2.1, 0.5 Hz, 1H), 4.34-4.25 (m, 4H).

Step c: To a solution of 6-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine(705 mg, 3.02 mmol), bis(pinacolato)diboron (1.53 g, 6.04 mmol), andpotassium acetate (890 mg, 9.06 mmol) in 1,4-dioxane (15 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (244 mg, 0.299 mmol). The mixture was heated at 100° C.and stirred for 3 h. After cooling to room temperature, water (30 mL)was added and the reaction mixture was extracted with EtOAc (3×25 mL).The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 10% EtOAc in hexanes) to obtain2-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (400 MHz, Methanol-d₄) δ 7.19-7.02 (m, 1H), 6.63 (ddd, J=8.4,1.5, 0.6 Hz, 1H), 4.36-4.22 (m, 4H), 1.32 (d, J=0.6 Hz, 12H).

Step d: To a solution of5-[[5-[(1S)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(100 mg, 0.20 mmol) in 1,2-dimethoxyethane (4 mL) and aqueous 2M K₂CO₃(0.40 mL, 0.80 mmol) was added2-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(120 mg, 0.41 mmol) and the resulting mixture was bubbled with nitrogengas for a few minutes. Tetrakis(triphenylphosphine)palladium(0) (25 mg,0.020 mmol) was then added and the reaction mixture was stirred at 80°C. of or 1 h. After cooling to room temperature, the reaction mixturewas diluted with EtOAc (30 mL) and washed with water (20 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The crude product was purified by flash chromatography (SiO₂, 30% EtOAcin hexanes) to obtain5-[[4-chloro-5-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₃₁H₂₂ClFN₂O₅ [M+H]⁺ 557.1, found 557.4.

Step e: To a solution of5-[[4-chloro-5-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(47 mg, 0.084 mmol) in DMF (3 mL) was added L-serine (70 mg, 0.67 mmol)and sodium triacetoxyborohydride (90 mg, 0.42 mmol). The resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/i-PrOH (30 mL), washed with water (15mL), dried (MgSO₄), and concentrated in vacuo. The crude residue waspurified by reverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) toobtain(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid as a di-trifluoroacetic acid salt, dr: ˜3.5:1. MS: (ES) m/zcalculated for C₃₄H₂₉ClFN₃O₇ [M+H]⁺ 646.2, found 646.4. ¹H NMR (400 MHz,Methanol-d₄) δ 8.99 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.43 (s, 1H), 7.53(s, 1H), 7.39-7.18 (m, 2H), 7.09 (s, 1H), 6.84-6.69 (m, 3H), 6.05-5.98(m, 1H), 5.37 (s, 2H), 4.38 (d, J=13.1 Hz, 1H), 4.35-4.27 (m, 4H), 4.01(s, 4H), 3.07-2.90 (m, 1H), 2.90-2.69 (m, 1H), 2.65-2.43 (m, 1H),2.25-1.97 (m, 1H).

Example 32: Synthesis of(2S,3R)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid

Synthesis of(2S,3R)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid was performed in an analogous route to Example 24, substitutingL-threonine for L-serine in Step b. dr: ˜3.5:1. MS: (ES) m/z calculatedfor C₃₃H₂₉ClFN₃O₅ [M+H]⁺ 602.2, found 602.5. ¹H NMR (400 MHz,Methanol-d₄) δ 8.99 (s, 1H), 8.93 (s, 1H), 8.43 (t, J=2.0 Hz, 1H), 7.52(s, 1H), 7.44-7.32 (m, 3H), 7.32-7.25 (m, 2H), 7.24-7.17 (m, 2H), 7.09(s, 1H), 6.03 (dd, J=6.5, 4.3 Hz, 1H), 5.38 (s, 2H), 4.38 (d, J=13.2 Hz,1H), 4.28 (d, J=13.2 Hz, 1H), 4.06 (q, J=6.4 Hz, 1H), 3.59 (d, J=7.1 Hz,1H), 3.09-2.96 (m, 1H), 2.89-2.74 (m, 1H), 2.57 (dq, J=13.5, 6.3 Hz,1H), 2.14 (ddd, J=13.4, 8.6, 4.4 Hz, 1H), 1.32 (d, J=6.3 Hz, 3H).

Example 33: Synthesis of(2S)-2-[[5-chloro-2-(5-cyano-3-pyridyl)-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

Step a: To a solution of (R)-4-bromoindan-1-ol (5.0 g, 24 mmol) in1,2-dimethoxyethane (50 mL) and water (30 mL) was added2-fluorophenylboronic acid (4.3, 31 mmol) and K₂CO₃ (8.1 g, 59 mmol) andthe resulting mixture was bubbled with nitrogen gas for a few minutes.Tetrakis(triphenylphosphine)palladium(O) (0.81 g, 0.71 mmol) was added,and the reaction mixture was stirred at 80° C. overnight. After coolingto room temperature, the reaction mixture was diluted with EtOAc (50 mL)and washed with water (30 mL) and brine (30 mL). The organic layer wasdried (Na₂SO₄), filtered, and concentrated in vacuo. The crude productwas purified by flash chromatography (SiO₂, 30% EtOAc in hexanes) toobtain (1R)-4-(2-fluorophenyl)indan-1-ol. MS: (ES) m/z calculated forC₁₅H₁₃FO [M-OH]⁺ 211.1, found 211.2.

Step b: To a cooled (0° C.) solution of (R)-4-(2-fluorophenyl)indan-1-ol(5.4 g, 24 mmol), 5-chloro-2,4-dihydroxy-benzaldehyde (4.1 g, 24 mmol),and triphenylphosphine (6.2 g, 24 mmol) in THF (100 mL) was slowly addeddiisopropyl azodicarboxylate (4.8 g, 24 mmol) in THF (10 mL). Themixture was allowed to gradually warm to room temperature for two days.The volatiles were removed in vacuo and the resulting crude residue waspurified by flash chromatography (20% EtOAc in hexane) to afford5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-hydroxy-benzaldehyde.Approximately 22% of racemization was observed during the reaction andthe enantiomeric ratio of the obtained product was ˜3.5:1. MS: (ES) m/zcalculated for C₂₂H₁₆ClFO₃ [M+H]⁺ 383.1, found 383.3.

Step c: To a cooled (−78° C.) solution of5-chloro-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-hydroxy-benzaldehyde(1.0 g, 2.6 mmol) in dichloromethane (10 mL) was sequentially addedpyridine (1.0 mL, 12 mmol) and triflic anhydride (0.87 mL, 5.2 mmol).The reaction mixture was allowed to warm to room temperature. After 2 h,the reaction was quenched by the careful addition of few milliliters ofsaturated aqueous NaHCO₃. The mixture was diluted with water (30 mL) andextracted with dichloromethane (3×20 mL). The combined organic layerswere dried (MgSO₄), filtered, and concentrated in vacuo. The crudeproduct was purified by flash chromatography (SiO₂, 20% EtOAc inhexanes) to obtain[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenyl]trifluoromethanesulfonate. MS: (ES) m/z calculated for C₂₃H₁₅ClF₄O₅S[M+Na]⁺ 537.0, found 537.2.

Step d: To a solution of[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenyl]trifluoromethanesulfonate (100 mg, 0.19 mmol) in 1,2-dimethoxyethane (3mL) and 2M K₂CO₃ (0.30 mL, 0.60 mmol) was added5-cyanopyridine-3-boronic acid (35 mg, 0.23 mmol), and the resultingmixture was bubbled with nitrogen gas for a few minutes.Tetrakis(triphenylphosphine)palladium(0) (44 mg, 0.038 mmol) was added,and the reaction mixture was stirred at 70° C. overnight. After coolingto room temperature, the reaction mixture was diluted withdichloromethane (20 mL) and washed with water (20 mL). The organic layerwas dried (MgSO₄), filtered, and concentrated in vacuo. The crudeproduct was purified by flash chromatography (SiO₂, 30% EtOAc inhexanes) to obtain(5-[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₈H₁₈ClFN₂O₂ [M+H]⁺ 469.1, found 469.4.

Step e: To a solution of(5-[4-chloro-5-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenyl]pyridine-3-carbonitrile(30 mg, 0.064 mmol) in DMF (2 mL) was added L-serine (60 mg, 0.57 mmol)and sodium triacetoxyborohydride (60 mg, 0.28 mmol). The resultingsuspension was stirred at room temperature overnight. The reactionmixture was diluted with 2:1 CHCl₃/i-PrOH (30 mL), washed with water (15mL), dried (MgSO₄), filtered, and concentrated in vacuo. The cruderesidue was purified by reverse phase preparative HPLC (CH₃CN—H₂O with0.1% TFA) to obtain((2S)-2-[[5-chloro-2-(5-cyano-3-pyridyl)-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid as a di-trifluoroacetic acid salt. dr: ˜3.5:1. MS: (ES) m/zcalculated for C₃₁H₂₅ClFN₃O₄ [M+H]⁺ 558.2, found 558.4. ¹H NMR (400 MHz,Methanol-d₄) δ 8.99 (s, 1H), 8.88 (s, 1H), 8.37 (s, 1H), 7.87 (s, 1H),7.54-7.11 (m, 8H), 6.05 (s, 1H), 4.23 (s, 2H), 4.03-3.84 (m, 3H),3.07-2.92 (m, 1H), 2.90-2.76 (m, 1H), 2.67-2.49 (m, 1H), 2.23-2.08 (m,1H).

Example 34: Synthesis of(2S,3R)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1R)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid

Step a: To a 1-L three-neck round bottom flask equipped with an internalthermometer under nitrogen was added(R)-(+)-2-methyl-CBS-oxazaborolidine (3.2 mL, 3.2 mmol, 1M THF) andborane-dimethyl sulfide (1.6 mL, 3.2 mmol, 2M THF) at room temperature.The mixture was stirred for 10 min then diluted with dichloromethane(100 mL). Borane-dimethyl sulfide (60 mL, 120 mmol, 2M THF) was added atroom temperature and the mixture was cooled to −30° C. A solution of4-bromoindan-1-one (5.0 g, 23.6 mmol) in dichloromethane (50 mL) wasadded slowly over 25 min while maintaining the internal temperaturebetween −30° C. and −20° C. After 1 h, the reaction was quenchedcarefully by the dropwise addition of methanol (50 mL). The solvent wasremoved in vacuo and the crude solid was purified by flashchromatography (15% EtOAc in hexane). The resulting purified solid wasrecrystallized from 1:5 EtOAc/hexane (100 mL) to give the product with98.2% ee. Enantiomeric excess was determined by integration of peaksthat were separated on a RegisCell 250×4.6 mm column at a flow rate of1.2 mL/min and an isochratic mobile phase of 5% isopropanol in hexane.MS: (ES) m/z calculated for C₉H₉BrO [M-OH+H]⁺ 197.0, found 197.2. ChiralHPLC: (S)-4-bromoindan-1-ol was eluted using 5% IPA in hexane:t_(R)=6.62 min.

Step b: To a cooled (0° C.) solution of (S)-4-bromoindan-1-ol (1.7 g,7.9 mmol), 5-chloro-2,4-dihydroxy-benzaldehyde (1.3 g, 7.9 mmol), andtriphenylphosphine (2.1 g, 7.9 mmol) in THE (25 mL) was slowly addeddiisopropyl azodicarboxylate (1.7 mL, 8.7 mmol) in THE (5 mL). Themixture was allowed to gradually warm to room temperature for threedays. The volatiles were removed in vacuo and the resulting cruderesidue was purified by flash chromatography (20% EtOAc in hexane) toafford 4-[(1R)-4-bromoindan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde.Approximately 17% of racemization was observed during the reaction andthe enantiomeric ratio of the obtained product was ˜5:1. MS: (ES) m/zcalculated for C₁₆H₁₂BrClO₃ [M−H]⁻ 365.0, found 365.1.

Step c: To a solution of4-[(1R)-4-bromoindan-1-yl]oxy-5-chloro-2-hydroxy-benzaldehyde (0.84 g,2.29 mmol) in DMF (12 mL) was added 5-(bromomethyl)nicotinonitrile (0.54g, 2.75 mmol), followed by Cs₂CO₃ (1.5 g, 4.58 mmol). After stirring atroom temperature overnight, the reaction mixture was diluted with 2:1CHCl₃/i-PrOH (30 mL) and washed with water (20 mL). The aqueous layerwas re-extracted with 2:1 CHCl₃/i-PrOH (2×15 mL). The combined organiclayers were dried (MgSO₄), filtered, and concentrated in vacuo. Thecrude was suspended in 1:1 CH₂Cl₂/hexanes (10 mL) and filtered to obtain5-[[5-[(1R)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₃H₁₆BrCN₂O₃ [M+H]⁺ 483.0, found 483.2.

Step d: To a solution of5-[[5-[(1R)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile(282 mg, 0.58 mmol) in 1,2-dimethoxyethane (4 mL) was added2-fluorophenylboronic acid (122 mg, 0.87 mmol), aqueous 2M K₂CO₃ (1.30mL, 2.58 mmol) and the resulting mixture was bubbled with nitrogen gasfor a few minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg,0.086 mmol) was then added and the reaction mixture was stirred at 80°C. overnight. After cooling to room temperature, the reaction mixturewas diluted with EtOAc (30 mL) and washed with water (30 mL) and brine(30 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, 30% EtOAc in hexanes) to obtain5-[[4-chloro-5-[(1R)-4-(2-fluorophenyl)indan-1-yl]oxy-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile.MS: (ES) m/z calculated for C₂₉H₂₀ClFN₂O₃ [M+H]⁺ 499.1, found 499.1.

Step e: To a solution of5-[[4-chloro-2-formyl-5-[(1R)-4-phenylindan-1-yl]oxy-phenoxy]methyl]pyridine-3-carbonitrile(31 mg, 0.062 mmol) in DMF (2 mL) was added L-threonine (50 mg, 0.42mmol) and sodium triacetoxyborohydride (100 mg, 0.47 mmol). Afterstirring at room temperature overnight, the reaction mixture wasconcentrated and the crude residue was purified by reverse phasepreparative HPLC (CH₃CN—H₂O with 0.1% TFA). The fractions were combinedand diluted with 2:1 CHCl₃/i-PrOH (30 mL). The organic layer was washedwith saturated aqueous NaHCO₃ (15 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to obtain(2S,3R)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1R)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanoicacid, dr: ˜5:1. MS: (ES) m/z calculated for C₃₃H₂₉ClFN₃O₅ [M+H]⁺ 602.2,found 602.5. ¹H NMR (400 MHz, Methanol-d₄) 9.00 (s, 1H), 8.91 (s, 1H),8.46 (t, J=1.9 Hz, 1H), 7.50-7.44 (m, 1H), 7.44-7.33 (m, 3H), 7.33-7.29(m, 2H), 7.29-7.16 (m, 2H), 7.06 (s, 1H), 6.00 (dd, J=6.3, 4.4 Hz, 1H),5.47-5.26 (m, 2H), 4.35-4.05 (m, 1H), 3.99-3.88 (m, 1H), 3.18 (d, J=6.7Hz, 1H), 3.02 (ddd, J=16.3, 8.3, 5.5 Hz, 1H), 2.82 (ddd, J=16.3, 8.2,5.6 Hz, 1H), 2.63-2.46 (m, 1H), 2.13 (ddt, J=13.3, 8.6, 5.3 Hz, 1H),1.29 (d, J=8.2 Hz, 3H).

Example 35: Synthesis of(2S,3R)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanamide

Synthesis of(2S,3R)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-butanamidewas performed in an analogous route to Example 24, substituting(2S,3R)-2-amino-3-hydroxybutanamide hydrochloride for L-serine in Stepb. dr: ˜3.5:1. MS: (ES) m/z calculated for C₃₃H₃₀ClFN₄O₄ [M+H]⁺ 601.2,found 601.2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.96 (d, J=2.0 Hz, 1H),8.90 (d, J=2.0 Hz, 1H), 8.38 (dd, J=2.4, 1.8 Hz, 1H), 7.44-7.32 (m, 4H),7.32-7.25 (m, 3H), 7.25-7.16 (m, 1H), 6.96 (s, 1H), 6.01-5.85 (m, 1H),5.29 (d, J=2.4 Hz, 2H), 3.80 (d J=13.5 Hz, 1H), 3.77 (t, J=6.4 Hz, 1H),3.69 (d, J=13.4 Hz, 1H), 3.10-2.97 (m, 1H), 2.95 (d, J=6.7 Hz, 1H),2.88-2.73 (m, 1H), 2.51 (m, 1H), 2.15 (m, 1H), 1.17 (d, J=6.4 Hz, 3H).

Example 36: Synthesis of(2S)-2-[[5-chloro-4-[(1S)-4-(5-chloro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-2-[(5-cyano-3-pyridyl)methoxy]phenyl]methylamino]-3-hydroxy-propanoicacid

Synthesis of(2S)-2-[[5-chloro-4-[(1S)-4-(5-chloro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-2-[(5-cyano-3-pyridyl)methoxy]phenyl]methylamino]-3-hydroxy-propanoicacid was performed in an analogous route to Example 31, substituting3-chlorocatechol for 3-fluorocatechol in Step a. dr: ˜3.5:1. MS: (ES)m/z calculated for C₃₄H₂₉C₂N₃O₇ [M+H]⁺ 662.2, found 662.1. ¹H NMR (400MHz, Methanol-d₄) δ 9.00 (s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 7.50 (s,1H), 7.29 (dt, J=14.9, 7.5 Hz, 2H), 7.16 (d, J=7.5 Hz, 1H), 7.06 (s,1H), 6.87 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 6.06-5.92 (m, 1H), 5.39 (s,2H), 4.39-4.35 (m, 3H), 4.35-4.18 (m, 3H), 4.03-3.88 (m, 1H), 3.89-3.76(m, 1H), 3.62-3.49 (m, 1H), 3.02-2.86 (m, 1H), 2.82-2.64 (m, 1H),2.57-2.45 (m, 1H), 2.17-1.92 (m, 1H).

Example 37: Synthesis of(2S)-2-[[2-[[3,5-bis(methylsulfonyl)phenyl]methoxy]-5-chloro-4-[(1)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 718.1 [M+H], ¹H NMR (400 MHz, Methanol-d₄) δ 8.47 (dd,J=9.4, 1.6 Hz, 3H), 7.53 (s, 1H), 7.46-7.33 (m, 2H), 7.33-7.15 (m, 5H),7.08 (s, 1H), 6.01 (dd, J=6.6, 4.4 Hz, 1H), 5.50 (s, 2H), 4.51-4.23 (m,2H), 4.11-3.95 (m, 3H), 3.06-2.96 (m, 1H), 2.88-2.78 (m, 1H), 2.62-2.52(m, 1H), 2.17-2.08 (m, 1H).

Example 38: Synthesis of((2S)-2-[[5-chloro-2-[(3,5-dicyanophenyl)methoxy]-4-[(1S)-4-(2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 652.1 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.27 (s, 2H),8.19 (s, 1H), 7.51 (s, 1H), 7.33-7.19 (m, 3H), 6.99 (s, 1H), 6.95-6.84(m, 3H), 5.95 (dd, J=6.4, 4.3 Hz, 1H), 5.37 (s, 2H), 4.39 (d, J=13.1 Hz,1H), 4.27 (s, 4H), 4.00 (dd, J=11.9, 3.9 Hz, 1H), 3.86 (dd, J=11.9, 6.9Hz, 1H), 3.59 (dd, J=6.9, 3.9 Hz, 1H), 3.39-3.11 (m, 2H), 2.96 (ddd,J=16.2, 8.2, 5.5 Hz, 1H), 2.56-2.43 (m, 1H), 2.17-2.04 (m, 1H).

Example 39: Synthesis of(2S)-2-[[5-chloro-2-[(3,5-dicyanophenyl)methoxy]-4-[(1S)-4-(2-fluoro-3-methoxy-phenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 642.1 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.24 (s, 2H),8.19 (s, 1H), 7.53 (s, 1H), 7.37-7.24 (m, 3H), 7.20-7.08 (m, 2H), 7.02(s, 1H), 6.93-6.84 (m, 1H), 6.01 (t, J=5.5 Hz, 1H), 5.35 (s, 2H),4.44-4.28 (m, 2H), 4.01 (s, 3H), 3.91 (d, J=2.0 Hz, 3H), 3.05-2.95 (m,1H), 2.88-2.78 (m, 1H), 2.60-2.49 (m, 1H), 2.18-2.08 (m, 1H).

Example 40: Synthesis of(2S)-2-[[5-chloro-2-[(3,5-dicyanophenyl)methoxy]-4-[(1S)-4-(2-fluorophenyl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 612.1 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.24 (s, 2H),8.19 (d, J=2.1 Hz, 1H), 7.53 (s, 1H), 7.47-7.14 (m, 7H), 7.03 (s, 1H),6.01 (t, J=5.4 Hz, 1H), 5.36 (s, 2H), 4.47-4.25 (m, 2H), 3.99 (dd,J=16.6, 4.2 Hz, 3H), 3.08-2.98 (m, 1H), 2.88-2.78 (m, 1H), 2.60-2.48 (m,1H), 2.18-2.08 (m, 1H).

Example 41: Synthesis of(2S)-2-[[5-chloro-2-[(3,5-dicyanophenyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-2-methyl-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 684.1 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.26 (s, 2H),8.19 (s, 1H), 7.56 (s, 1H), 7.34-7.21 (m, 3H), 7.03 (s, 1H), 6.75 (d,J=6.3 Hz, 2H), 6.01 (t, J=5.3 Hz, 1H), 5.35 (d, J=3.8 Hz, 2H), 4.33 (d,J=2.0 Hz, 6H), 4.04 (d, J=12.1 Hz, 1H), 3.88-3.80 (m, 1H), 3.09-2.96 (m,1H), 2.88-2.78 (m, 1H), 2.58-2.48 (m, 1H), 2.20-2.08 (m, 1H), 1.56 (d,J=1.7 Hz, 3H), 1.27 (d, J=7.5 Hz, 1H).

Example 42: Synthesis of(2S)-2-[[5-chloro-2-[(3,5-dicyanophenyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 670.0 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.24 (dd,J=1.4, 0.8 Hz, 2H), 8.19 (t, J=1.5 Hz, 1H), 7.52 (s, 1H), 7.37-7.18 (m,3H), 7.01 (s, 1H), 6.84-6.69 (m, 2H), 6.07-5.94 (m, 1H), 5.35 (s, 2H),4.48-4.23 (m, 6H), 4.09-3.85 (m, 3H), 3.07-2.97 (m, 1H), 2.88-2.78 (m,1H), 2.58-2.48 (m, 1H), 2.18-2.08 (m, 1H).

Example 43: Synthesis of(2S)-2-[[5-chloro-2-[(3,5-dicyanophenyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11. MS: 646.2 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (s,1H), 8.91 (s, 1H), 8.45 (s, 1H), 7.49 (s, 1H), 7.34-7.21 (m, 3H), 7.04(s, 1H), 6.80 (d, J=6.8 Hz, 1H), 6.70 (d, J=10 Hz, 1H), 5.98 (br s, 1H),5.38 (s, 2H), 4.37-4.17 (m, 6H), 4.01-3.78 (m, 2H), 3.52 (s, 1H),3.08-2.97 (m, 1H), 2.88-2.78 (m, 1H), 2.58-2.48 (m, 1H), 2.16-2.06.

Example 44: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 646.2 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d,J=2.1 Hz, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.45 (t, J=2.1 Hz, 1H), 7.51 (d,J=0.9 Hz, 1H), 7.36-7.21 (m, 3H), 7.05 (s, 1H), 6.81-6.70 (m, 2H),6.03-5.96 (m, 1H), 5.38 (s, 2H), 4.40-4.29 (m, 5H), 4.25 (d, J=13.1 Hz,1H), 3.99 (dd, J=11.9, 3.9 Hz, 1H), 3.84 (dd, J=11.8, 7.1 Hz, 1H), 3.55(dd, J=7.1, 3.9 Hz, 1H), 3.02 (dt, J=14.1, 8.0 Hz, 1H), 2.88-2.76 (m,1H), 2.57-2.49 (m, 1H), 2.15-2.05 (m, 1H).

Example 45: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-2-methyl-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 660.1 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d,J=2.1 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.46 (t, J=2.2 Hz, 1H), 7.56 (s,1H), 7.39-7.20 (m, 3H), 7.06 (s, 1H), 6.83-6.69 (m, 2H), 6.05-5.96 (m,1H), 5.38 (d, J=3.2 Hz, 2H), 4.33 (s, 4H), 4.25 (s, 2H), 3.94 (d, J=12.1Hz, 1H), 3.74 (d, J=12.0 Hz, 1H), 3.10-2.96 (m, 1H), 2.90-2.76 (m, 1H),2.62-2.47 (m, 1H), 2.19-2.05 (m, 1H), 1.46 (s, 3H).

Example 46: Synthesis of(5-chloro-4-(((S)-4-(5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)benzyl)-L-serine

The title compound was prepared by following an analogous route toExample 3. MS: 699.0.1 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ ¹H NMR(400 MHz, Methanol-d₄) δ 9.08 (dd, J=21.4, 2.1 Hz, 2H), 8.54 (t, J=2.1Hz, 1H), 7.53 (s, 1H), 7.37-7.21 (m, 3H), 7.11 (s, 1H), 6.81-6.70 (m,2H), 6.02 (dd, J=6.5, 4.4 Hz, 1H), 5.44 (s, 2H), 4.34 (d, J=15.1 Hz,6H), 4.01 (s, 2H), 3.24 (s, 3H), 3.02 (ddd, J=16.2, 8.5, 5.5 Hz, 1H),2.89-2.77 (m, 1H), 2.57 (td, J=13.6, 6.2 Hz, 1H), 2.19-2.07 (m, 1H).

Example 47: Synthesis of(2S)-2-[[5-chloro-2-[(5-cyano-3-pyridyl)methoxy]-4-[(1S)-4-(5,6-difluoro-2,3-dihydro-1,4-benzodioxin-7-yl)indan-1-yl]oxy-phenyl]methylamino]-3-hydroxy-propanoicacid

The title compound was prepared by following an analogous route toExample 11, using the optically enriched intermediate described inScheme 3. MS: 664.0 [M+H]; ¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d,J=2.1 Hz, 1H), 8.90 (d, J=1.9 Hz, 1H), 8.45 (t, J=2.0 Hz, 1H), 7.49 (s,1H), 7.38-7.22 (m, 3H), 7.05 (s, 1H), 6.63 (dd, J=6.6, 2.4 Hz, 1H), 5.99(dd, J=6.5, 4.4 Hz, 1H), 5.38 (s, 2H), 4.39-4.27 (m, 5H), 4.20 (d,J=13.1 Hz, 1H), 3.96 (dd, J=11.6, 4.0 Hz, 1H), 3.82 (dd, J=11.7, 7.0 Hz,1H), 3.51 (dd, J=6.9, 4.1 Hz, 1H), 3.09-2.97 (m, 1H), 2.89-2.77 (m, 1H),2.61-2.48 (m, 1H), 2.23-2.06 (m, 1H).

Additional compounds prepared by methods analogous to the methodsdescribed above were made and are provided in Table 1A, Table 1B, andTable 1C.

TABLE 1A MS: (ES) Compound Structure ¹H NMR m/z (M + H)

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.92 (d, J =2.0 Hz, 1H), 8.43 (t, J = 2.1 Hz, 1H), 7.53 (s, 1H), 7.50-7.43 (m, 4H),7.40-7.29 (m, 4H), 7.12 (s, 1H), 6.04-5.99 (m, 1H), 5.39 (s, 2H), 4.35(q, J = 13.1 Hz, 2H), 4.01 (s, 3H), 3.24-3.15 (m, 1H), 3.06- 2.88 (m,1H), 2.61-2.44 (m, 1H), 2.26-2.07 (m, 1H). 570.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.94 (d, J =2.0 Hz, 1H), 8.41 (s, 1H), 7.52 (d, J = 11.5 Hz, 1H), 7.49-7.40 (m, 4H),7.38-7.33 (m, 2H), 7.31 (d, J = 5.0 Hz, 2H), 7.16-7.08 (m, 1H),6.07-5.94 (m, 1H), 5.42 (s, 2H), 4.43 (s, 2H), 4.38-4.22 (m, 4H), 3.65(td, J = 8.4 Hz, 1H), 3.26- 3.12 (m, 1H), 2.98 (ddd, J = 16.2, 8.2, 5.4Hz, 1H), 2.62-2.46 (m, 1H), 2.24-2.04 (m, 1H). 566.5

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.2 Hz, 1H), 8.93 (d, J =2.0 Hz, 1H), 8.43 (s, 1H), 7.60- 7.48 (m, 2H), 7.45-7.34 (m, 3H), 7.31(t, J = 7.3 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.11 (s, 1H), 6.08-5.96(m, 1H), 5.38 (s, 2H), 4.35 (q, J = 13.1 Hz, 2H), 4.05- 3.98 (m, 3H),3.02-2.84 (m, 1H), 2.83-2.66 (m, 1H), 2.66-2.48 (m, 1H), 2.19-2.06 (m,1H). 626.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.2 Hz, 1H), 8.92 (d, J =2.0 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 7.69-7.62 (m, 1H), 7.56 (dd, J =7.2, 3.3 Hz, 1H), 7.36-7.17 (m, 5H), 7.17-7.04 (m, 2H), 6.11- 5.96 (m,1H), 5.39 (s, 2H), 4.35 (q, J = 13.1 Hz, 2H), 4.07-4.00 (m, 3H),2.95-2.72 (m, 1H), 2.72- 2.60 (m, 1H), 2.60-2.47 (m, 1H), 2.17-2.05 (m,4H). 606.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.93 (d, J =2.0 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 7.53 (s, 1H), 7.50-7.44 (m, 1H),7.43-7.32 (m, 3H), 7.29 (d, J = 7.7 Hz, 1H), 7.26-7.14 (m, 1H),7.14-7.02 (m, 2H), 6.12- 5.92 (m, 1H), 5.39 (d, J = 1.3 Hz, 2H), 4.35(q, J = 13.1 Hz, 2H), 4.08-3.96 (m, 3H), 3.18-3.08 (m, 1H), 3.04-2.93(m, 1H), 2.66- 2.48 (m, 1H), 2.26-2.09 (m, 1H). 588.2

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.2 Hz, 1H), 8.93 (d, J =2.0 Hz, 1H), 8.43 (s, 1H), 7.53 (s, 1H), 7.43-7.24 (m, 4H), 7.11 (s,1H), 7.03 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H),6.05-5.97 (m, 1H), 5.39 (s, 2H), 4.35 (q, J = 13.0 Hz, 2H), 4.03-3.95(m, 3H), 3.84 (s, 3H), 3.23-3.13 (m, 1H), 3.10-2.77 (m, 1H), 2.65-2.45(m, 1H), 2.23- 2.10 (m, 1H). 600.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (t, J = 2.2 Hz 1H), 8.94 (dd, J =4.4 Hz, 2.1 Hz 1H), 8.42 (dt, J = 11 Hz, 0.94 Hz, 1H), 7.57 (s, 1H),7.44-7.17 (m, 7H), 7.13 (d, J = 7.2 Hz, 1H), 6.08-6.02 (m, 1H),5.43-5.39 (m, 2H), 4.54 (br s, 1H), 4.50 (s, 1H), 4.38 (s, 1H), 3.08-2.98 (m, 1H), 2.89-2.80 (m, 1H), 2.64-2.53 (m, 1H), 2.40-2.30 (m, 1H),2.18-2.07 (m, 1H), 2.03-1.95 (m, 1H). 570.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 1.8 Hz, 1H), 8.94 (d, J =2.0 Hz, 1H), 8.41 (s, 1H), 7.58 (s, 1H), 7.45-7.17 (m, 7H), 7.13 (s,1H), 6.05 (dd, J = 6.4 Hz, 4.4 Hz, 1H), 5.41 (s, 2H), 4.55-4.44 (m, 2H),3.51-3.41 (m, 1H), 2.90-2.79 (m, 1H), 2.65-2.53 (m, 2H), 2.20- 2.09 (m,2H). 614.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.2 Hz, 1H), 8.92 (d, J =2.0 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 7.53 (s, 1H), 7.39-7.22 (m, 3H),7.10 (s, 1H), 6.98-6.81 (m, 3H), 6.05-5.81 (m, 1H), 5.38 (s, 2H), 4.34(q, J = 13.1 Hz, 2H), 4.28 (d, J = 0.5 Hz, 4H), 4.02-3.99 (m, 3H),3.21-3.05 (m, 1H), 3.06-2.81 (m, 1H), 2.74-2.46 (m, 1H), 2.27- 1.97 (m,1H). 628.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (d, J = 1.8 Hz 1H), 8.95 (d, J =1.8 Hz, 1H), 8.41 (s, 1H), 7.56 (s, 1H), 7.45-7.17 (m, 7H), 7.15-7.11(m, 1H), 6.08-6.03 (m, 1H), 5.40 (s, 2H), 4.41-4.17 (m, 2H), 4.13 (s,1H), 3.51-3.34 (m, 1H), 3.11-2.96 (m, 2H), 2.92-2.80 (m, 1H), 2.65- 2.54(m, 1H), 2.27-1.98 (m, 2H), 1.87-1.58 (m, 2H). 584.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (d, J = 2.0 Hz 1H), 8.94 (d, J =2.0 Hz, 1H), 8.40 (t, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.44-7.30 (m, 5H),7.29-7.17 (m, 2H), 7.12 (s, 1H), 6.05 (dd, J = 6.4 Hz, 4.4 Hz, 1H),5.43-5.40 (m, 2H), 4.32 (s, 2H), 3.08-2.98 (m, 1H), 2.89-2.80 (m, 7H),2.62-2.52 (m, 1H), 2.17- 2.08 (m, 1H). 528.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.0 Hz, 1H), 8.94 (d, J =2.0 Hz, 1H), 8.41 (m, 1H), 7.56 (s, 1H), 7.45-7.16 (m, 7H), 7.13 (s,1H), 6.05 (dd, J = 6.4 Hz, 4.4 Hz, 1H), 5.41 (s, 2H), 4.47-4.38 (m, 2H),3.72-3.50 (m, 2H), 3.07-2.99 (m, 1H), 2.89-2.79 (m, 1H), 2.63- 2.54 (m,1H), 2.42-2.07 (m, 3H). 598.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.90 (s, 1H), 8.87 (m, 1H), 8.31 (m,1H), 7.43 (d, J = 5.2 Hz, 1H), 7.39-7.22 (m, 5H), 7.21-7.09 (m, 2H),7.05 (d, J = 2.2 Hz, 1H), 6.00- 5.96 (m, 1H), 5.40 (s, 2H), 4.70- 4.53(m, 1H), 4.43-4.29 (m, 4H), 4.02-3.89 (m, 2H), 3.22-3.19 (m, 1H),3.01-2.93 (m, 1H), 2.59-2.48 (m, 1H), 2.17-2.07 (m, 1H). 556.3

¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s, 1H), 7.35 (q, J = 4.1 Hz, 1H),7.32-7.27 (m, 2H), 7.01 (s, 1H), 6.97-6.87 (m, 3H), 6.04 (t, J = 5.5 Hz,1H), 4.27 (s, 4H), 3.92 (s, 2H), 3.87 (s, 3H), 3.71 (dd, J = 11.2, 4.6Hz, 1H), 3.61 (dd, J = 11.2, 6.4 Hz, 1H), 3.15 (dd, J = 6.4, 4.5 Hz,1H), 3.09 (ddd, J = 13.7, 8.6, 4.3 Hz, 1H), 2.99-2.85 (m, 1H), 2.56 (dq,J = 13.4, 6.5, 6.0 Hz, 1H), 2.09-1.98 (m, 1H). 548.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.92 (d, J =2.0 Hz, 1H), 8.43 (t, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.44-7.29 (m, 3H),7.15-7.01 (m, 2H), 6.94 (dt, J = 9.0, 3.5 Hz, 1H), 6.86 (dd, J = 6.0,3.2 Hz, 1H), 6.11-6.00 (m, 1H), 5.38 (s, 2H), 4.34 (q, J = 13.1 Hz, 2H),4.01 (s, 3H), 3.81 (d, J = 0.7 Hz, 3H), 3.11-2.96 (m, 1H), 2.92-2.79 (m,1H), 2.59 (dt, J = 13.0, 6.4 Hz, 1H), 2.20-2.04 (m, 1H). 618.5

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, 1H), 8.92 (d, J = 2.0 Hz, 1H),8.43 (t, J = 2.1 Hz, 1H), 7.53 (s, 1H), 7.39-7.34 (m, 1H), 7.32 (d, J =7.5 Hz, 1H), 7.30-7.29 (m, 1H), 7.29-7.21 (m, 2H), 7.15 (td, J = 7.4,6.8, 4.9 Hz, 2H), 7.11 (d, J = 2.6 Hz, 1H), 6.04 (dd, J = 6.5, 4.3 Hz,1H), 5.38 (d, J = 2.3 Hz, 2H), 4.35 (q, J = 13.1 Hz, 2H), 4.10- 3.95 (m,3H), 3.09-2.96 (m, 1H), 2.87-2.74 (m, 1H), 2.57 (dq, J = 13.7, 6.6 Hz,1H), 2.33 (d, J = 1.9 Hz, 3H), 2.14 (td, J = 8.5, 3.7 Hz, 1H). 602.5

¹H NMR (400 MHz, Methanol-d₄) δ 9.04-8.95 (m, 1H), 8.92 (d, J = 2.0 Hz,1H), 8.43 (q, J = 2.0 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.34 (dd, J =8.4, 4.9 Hz, 1H), 7.24- 7.09 (m, 3H), 7.08-6.97 (m, 1H), 6.95-6.80 (m,1H), 6.20 (dd, J = 6.3, 1.9 Hz, 1H), 5.37 (d, J = 2.0 Hz, 2H), 4.47-4.22(m, 2H), 4.00 (s, 3H), 3.91 (s, 3H), 3.22- 2.98 (m, 1H), 2.79 (ddd, J =16.6, 8.6, 2.9 Hz, 1H), 2.58-2.38 (m, 1H), 2.36-2.11 (m, 1H). 636.3

¹H NMR (400 MHz, Methanol-d₄) δ 7.45 (s, 1H), 7.42 (d, 1H), 7.32 (t, J =7.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.20-7.14 (m, 1H), 7.12 (td, J = 8.0,1.9 Hz, 1H), 6.96 (d, J = 1.7 Hz, 1H), 6.89 (ddd, J = 7.5, 6.3, 1.8 Hz,1H), 6.00 (dd, J = 6.5, 4.4 Hz, 1H), 4.35 (d, J = 13.1 Hz, 1H),4.28-4.13 (m, 3H), 4.02 (dd, J = 4.3, 1.8 Hz, 2H), 3.96 (t, J= 4.2 Hz,1H), 3.91 (s, 3H), 3.08-2.94 (m, 1H), 2 88 2.73 (m, 1H), 2.59 (dq, J =13.7, 6.6 Hz, 1H), 2.16 552.4 (ddt, J = 13.3, 9.0, 4.9 Hz, 1H), 1.49 (t,J = 7.0 Hz, 3H).

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (s, 1H), 8.94 (d, J = 1.6 Hz, 1H),8.43-8.38 (m, 1H), 7.51 (s, 1H), 7.31-7.23 (m, 3H), 7.12-7.07 (m, 1H),6.94-6.88 (m, 3H), 6.01- 5.97 (m, 1H), 5.40 (s, 2H), 4.70- 4.53 (m, 1H),4.43-4.29 (m, 4H), 4.27 (s, 4H), 4.02-3.89 (m, 2H), 3.22-3.14 (m, 1H),3.01-2.93 (m, 1H), 2.59-2.48 (m, 1H), 2.17-2.07 (m, 1H). 596.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (d, J = 1.7 Hz, 1H), 8.94 (d, J =1.7 Hz, 1H), 8.43-8.41 (m, 1H), 7.51 (s, 1H), 7.38-7.27 (m, 3H),7.20-7.06 (m, 3H), 6.92-6.87 (m, 1H), 6.05-6.00 (m, 1H), 5.41-5.37 (m,2H), 4.60-4.53 (m, 1H), 4.43 (s, 1H), 4.38-4.28 (m, 3H), 4.00- 3.92 (m,2H), 3.91 (s, 3H), 3.06- 2.95 (m, 1H), 2.89-2.77 (m, 1H), 2.62-2.53 (m,1H), 2.17-2.07 (m, 1H). 586.3

¹H NMR (400 MHz, Methanol-d₄) δ 7.44 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H),7.30 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 6.95 (s, 1H),6.80-6.69 (m, 2H), 6.02-5.90 (m, 1H), 4.34-4.31 (m, 5H), 4.26- 4.11 (m,3H), 4.02 (t, J = 3.6 Hz, 2H), 3.94 (t, J = 4.2 Hz, 1H), 3.08- 2.96 (m,1H), 2.91-2.76 (m, 1H), 2.58 (s, 1H), 2.22-2.11 (m, 1H), 1.49 (t, J =7.0 Hz, 3H). 580.5

¹H NMR (400 MHz, Methanol-d₄) δ 8.97 (s, 1H), 8.95 (s, 1H), 8.38 (s,1H), 7.58-7.50 (m, 1H), 7.33 (t, J = 7.0 Hz, 1H), 7.27 (dd, J = 10.8,7.2 Hz, 2H), 7.10 (d, J = 3.5 Hz, 1H), 6.85-6.71 (m, 2H), 6.04 (t, J =5.5 Hz, 1H), 5.39 (d, J = 2.9 Hz, 2H), 4.35-4.32 (m, 4H), 4.31 (d, J =6.2 Hz, 3H), 4.05 (s, 1H), 3.83 (d, J = 16.3 Hz, 1H), 3.50 (d, J = 14.4Hz, 1H), 3.14-2.93 (m, 2H), 2.89-2.74 (m, 1H), 2.57 (d, J = 7.3 Hz, 1H),2.22-2.10 (m, 2H), 1.90 (s, 2H), 1.66 (d, J = 12.4 Hz, 1H). 642.5

¹H NMR (400 MHz, Methanol-d₄) δ 9.01 (s, 1H), 8.93 (s, 1H), 8.46 (s,1H), 7.57 (s, 1H), 7.53-7.12 (m, 7H), 7.05 (s, 1H), 6.01 (m, 1H), 5.44(s, 2H), 4.36 (s, 2H), 3.09 (m, 2H), 3.03 (m, 1H), 2.83 (m, 1H), 2.54(m, 1H), 2.06 (m, 1H). 594.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H),8.41 (s, 1H), 7.58 (s, 1H), 7.40-7.28 (m, 3H), 7.21-7.08 (m, 3H),6.93-6.87 (m, 1H), 6.08-6.03 (m, 1H), 5.40 (s, 2H), 4.71 (s, 1H),4.53-4.37 (m, 2H), 3.91 (s, 3H), 3.07-2.97 (m, 2H), 2.8-2.79 (m, 2H),2.65-2.53 (m, 2H), 2.20-2.09 (m, 2H). 644.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (s, 1H), 8.92 (s, 1H), 8.43 (s,1H), 7.53 (s, 1H), 7.43-7.35 (m, 2H), 7.33-7.27 (m, 1H), 7.21 (d, J =7.4 Hz, 1H), 7.10 (s, 1H), 6.98- 6.89 (m, 1H), 6.85 (s, 1H), 6.09- 5.96(m, 1H), 5.38 (s, 2H), 4.34 (q, J = 13.2 Hz, 2H), 4.04-3.96 (m, 3H),3.81 (s, 3H), 3.05-2.86 (m, 1H), 2.85-2.69 (m, 1H), 2.64- 2.45 (m, 1H),2.18-2.08 (m, 1H). 634.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.2 Hz, 1H), 8.92 (d, J =1.9 Hz, 1H), 8.43 (s, 1H), 7.53 (s, 1H), 7.37 (d, J = 7.1 Hz, 1H), 7.33(d, J = 7.4 Hz, 1H), 7.29 (d, J = 7.4 Hz, 2H), 7.23-7.14 (m, 1H), 7.09(d, J = 5.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.05-5.97 (m, 1H), 5.38(s, 2H), 4.35 (q, J = 13.1 Hz, 2H), 4.05-3.94 (m, 3H), 3.10- 2.90 (m,1H), 2.90-2.77 (m, 1H), 2.70-2.50 (m, 1H), 2.36 (s, 3H), 2.22-2.05 (m,1H). 602.5

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (s, 1H), 8.94 (s, 1H), 8.40 (d, J =12.4 Hz, 1H), 7.50 (d, J = 3.6 Hz, 1H), 7.35-7.22 (m, 3H), 7.08 (d, J =10.2 Hz, 1H), 6.78-6.71 (m, 2H), 6.02 (s, 1H), 5.39 (s, 2H), 4.41 (d, J= 20.7 Hz, 2H), 4.38- 4.24 (m, 6H), 4.04-3.82 (m, 2H), 3.71-3.55 (m,1H), 3.07-2.96 (m, 1H), 2.93-2.65 (m, 1H), 2.60- 2.48 (m, 1H), 2.18-2.06(m, 1H). 614.5

¹H NMR (400 MHz, Methanol-d) δ 9.00 (d, J = 1.9 Hz, 1H), 8.93 (d, J =1.9 Hz, 1H), 8.43 (br s, 1H), 7.54 (s, 1H), 7.42-7.27 (m, 3H), 7.21-7.09 (m, 3H), 6.93-6.87 (m, 1H), 6.05 (dd, J = 6.8 Hz, 4.4 Hz, 1H),5.46-5.34 (m, 2H), 4.56 (d, J = 13 Hz, 1H), 4.48 (br s, 1H), 4.43- 4.37(m, 2H), 3.50-3.44 (m, 1H), 3.08-2.97 (m, 1H), 2.89-2.79 (m, 1H),2.71-2.55 (m, 2H), 2.31-2.23 (m, 1H), 2.19-2.10 (m, 1H). 644.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.89 (d, J = 13.8 Hz, 2H), 7.53 (s, 1H),7.44-7.37 (m, 3H), 7.38- 7.30 (m, 2H), 7.31-7.23 (m, 1H), 7.23-7.16 (m,1H), 7.14 (s, 1H), 6.18-5.96 (m, 1H), 5.37-5.27 (m, 2H), 4.29 (dd, J =24.0, 7.4 Hz, 2H), 4.00 (d, J = 1.2 Hz, 3H), 3.10- 2.96 (m, 1H),2.92-2.79 (m, 1H), 2.71-2.51 (m, 1H), 2.23- 2.11 (m, 1H). 598.3

¹H NMR (400 MHz, Methanol-d₄) δ 9.00 (d, J = 2.2 Hz, 1H), 8.93 (d, J =2.0 Hz, 1H), 8.44 (s, 1H), 7.53 (s, 2H), 7.48-7.14 (m, 5H), 7.10 (s,2H), 6.15-5.93 (m, 1H), 5.39 (s, 2H), 4.32 (d, J = 12.9 Hz, 1H), 4.23(d, 13.0 Hz, 1H), 4.10- 3.83 (m, 1H), 3.14-2.92 (m, 1H), 2.94-2.75 (m,1H), 2.64-2.45 (m, 1H), 2.24-1.89 (m, 1H), 1.56 (d, J = 7.2 Hz, 3H).594.4

¹H NMR (400 MHz, Methanol-d₄) δ 9.00 (d, J = 2.1 Hz, 1H), 8.91 (d, J =2.0 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.29 (m, 5H),7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.19 (dd, J = 10.3, 8.3 Hz, 1H), 7.07(s, 1H), 6.00 (t, J = 5.4 Hz, 1H), 5.39 (d, J = 4.3 Hz, 2H), 4.39-4.29(m, 1H), 4.24 (d, J = 13.1 Hz, 1H), 4.01-3.94 (m, 1H), 3.83 (dd, J =11.8, 7.0 Hz, 1H), 3.54 (s, 1H), 3.02 (ddd, J = 14.5, 8.4, 5.6 Hz, 1H),2.88-2.75 (m, 1H), 2.56 (dt, J = 14.0, 7.6 Hz, 1H), 2.12 (ddd, J = 13.2,8.6, 4.4 Hz, 1H). 588.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.95 (dd, J = 22.8, 2.0 Hz, 2H), 8.42(t, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.44-7.24 (m, 3H), 7.24- 7.03 (m,3H), 6.89 (ddd, J = 8.0, 6.3, 1.9 Hz, 1H), 6.02 (dd, J = 6.6, 4.3 Hz,1H), 5.37 (d, J = 2.4 Hz, 2H), 4.44-4.15 (m, 2H), 4.12- 3.98 (m, 1H),3.91 (s, 3H), 3.64 (dd, J = 7.1, 1.1 Hz, 1H), 3.08- 2.92 (m, 1H),2.90-2.71 (m, 1H), 2.67-2.45 (m, 1H), 2.14 (tt, J = 8.3, 4.6 Hz, 1H),1.32 (d, J = 6.4 Hz, 3H). 632.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.92 (d, J =2.0 Hz, 1H), 8.43 (t, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.41-7.25 (m, 3H),7.22-7.06 (m, 3H), 6.89 (ddd, J = 7.9, 6.3, 1.9 Hz, 1H), 6.03 (dd, J =6.5, 4.4 Hz, 1H), 5.43- 5.31 (m, 2H), 4.42-4.27 (m, 2H), 4.01 (d, J =1.1 Hz, 3H), 3.91 (s, 3H), 3.08-2.96 (m, 1H), 2.89- 2.79 (m, 1H), 2.58(dq, J = 13.5, 6.4 Hz, 1H), 2.15 (ddd, J = 13.3, 8.9, 4.3 Hz, 1H). 618.4

¹H NMR (400 MHz, Methanol-d₄) δ 9.00 (d, J = 2.1 Hz, 1H), 8.93 (s, 1H),8.43 (s, 1H), 7.52 (d, J = 0.5 Hz, 1H), 7.45-7.29 (m, 4H), 7.27 (d, J =8.2 Hz, 1H), 7.20 (t, J = 9.4 Hz, 2H), 7.10 (s, 1H), 6.03 (d, J = 5.6Hz, 1H), 5.39 (s, 2H), 4.46- 4.16 (m, 3H), 4.08 (d, J = 6.6 Hz, 1H),3.13-2.95 (m, 1H), 2.89- 2.65 (m, 1H), 2.65-2.44 (m, 4H), 2.32-2.02 (m,1H). 630.5

¹H NMR (400 MHz, Methanol-d₄) δ 9.01 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H),8.47 (s, 1H), 7.50 (s, 1H), 7.42-7.35 (m, 3H), 7.33-7.29 (m, 2H), 7.27(dd, J = 7.5, 1.2 Hz, 1H), 7.21 (dd, J = 18.2, 8.7 Hz, 1H), 7.12 (d, J =1.8 Hz, 1H), 6.09- 6.02 (m, 1H), 5.41 (d, J = 4.8 Hz, 2H), 4.43-4.25 (m,4H), 3.07- 2.96 (m, 2H), 2.84 (dd, J = 17.5, 8.3 Hz, 2H), 2.68-2.49 (m,1H), 2.27-2.09 (m, 1H). 615.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.93 (d, J =2.0 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 7.52 (s, 1H), 7.42-7.34 (m, 4H),7.31 (s, 1H), 7.30-7.16 (m, 2H), 7.09 (d, J = 0.8 Hz, 1H), 6.08-5.89 (m,1H), 5.39 (d, J = 3.9 Hz, 2H), 4.39 (d, J = 13.2 Hz, 1H), 4.32-4.24 (m,1H), 4.12- 3.97 (m, 1H), 3.64 (d, J = 7.1 Hz, 1H), 3.11-2.97 (m, 1H),2.97- 2.75 (m, 1H), 2.67-2.43 (m, 1H), 2.26-2.07 (m, 1H), 1.32 (d, J =6.3 Hz, 3H). 602.5

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (d, J = 2.1 Hz, 1H), 8.93 (d, 1.8Hz, 1H), 8.41 (s, 1H), 7.53 (d, J = 0.7 Hz, 1H), 7.45-7.30 (m, 5H),7.30-7.22 (m, 1H), 7.23- 7.15 (m, 1H), 7.10 (s, 1H), 6.10- 5.98 (m, 1H),5.37 (d, J = 3.4 Hz, 2H), 4.37 (d, J = 13.3 Hz, 1H), 4.32- 4.20 (m, 2H),3.90 (d, J = 3.6 Hz, 1H), 3.10-2.98 (m, 1H), 2.91- 2.75 (m, 1H),2.66-2.50 (m, 1H), 2.14 (d, J = 5.1 Hz, 1H), 1.23 (dd, J = 6.5, 0.7 Hz,3H). 602.4

¹H NMR (400 MHz, Methanol-d₄) δ 8.98 (d, J = 2.1 Hz, 1H), 8.93 (d, J =2.1 Hz, 1H), 8.41 (t, J = 2.1 Hz, 1H), 7.53 (s, 1H), 7.45-7.31 (m, 5H),7.30-7.23 (m, 1H), 7.23- 7.16 (m, 1H), 7.11 (s, 1H), 6.07- 6.00 (m, 1H),5.38 (d, J = 2.4 Hz, 2H), 4.37 (d, J = 13.2 Hz, 1H), 4.34-4.24 (m, 2H),3.90 (d, J = 3.6 Hz, 1H), 3.07-2.97 (m, 1H), 2.92-2.73 (m, 1H),2.73-2.50 (m, 1H), 2.28-2.06 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H). 602.5

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (s, 1H), 8.90 (s, 1H), 8.45 (s,1H), 7.50 (s, 1H), 7.42-7.38 (m, 3H), 7.35 (d, J = 8.2 Hz, 1H), 7.32-7.30 (m, 1H), 7.28-7.23 (m, 1H), 7.20 (t, J = 9.4 Hz, 1H), 7.06 (s, 1H),6.08-5.95 (m, 1H), 5.38 (s, 2H), 4.43-4.09 (m, 2H), 3.97 (s, 1H), 3.83(s, 1H), 3.57-3.53 (m, 1H), 3.05-2.99 (m, 1H), 2.97- 2.68 (m, 1H),2.63-2.44 (m, 1H), 2.25-2.00 (m, 1H). 588.4

¹H NMR (400 MHz, Methanol-d₄) δ 9.02-8.93 (m, 1H), 8.91 (d, J = 2.0 Hz,1H), 8.48 (t, J = 2.0 Hz, 1H), 8.07-7.93 (m, 1H), 7.69- 7.50 (m, 1H),7.51-7.12 (m, 6H), 7.04 (s, 1H), 6.10-5.93 (m, 1H), 5.33 (d, J = 2.1 Hz,2H), 4.20- 3.91 (m, 2H), 3.85 (d, J = 4.4 Hz, 2H), 3.73 (d, J = 0.9 Hz,3H), 3.40 (d, J = 1.5 Hz, 1H), 3.09-2.92 (m, 1H), 2.90-2.74 (m, 1H),2.62- 2.46 (m, 1H), 2.27-2.03 (m, 1H). 602.3

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (s, 1H), 8.91 (s, 1H), 8.43 (s,1H), 7.51 (s, 1H), 7.48-7.10 (m, 7H), 7.04 (s, 1H), 5.99 (s, 1H), 5.39(s, 2H), 4.20 (s, 2H), 3.58-3.51 (m, 1H), 3.05-2.91 (m, 1H), 2.97- 2.74(m, 1H), 2.63-2.48 (m, 1H), 2.25-2.06 (m, 1H), 1.53- 1.40 (m, 3H). 594.2

¹H NMR (400 MHz, Methanol-d₄) δ 8.99 (d, J = 2.1 Hz, 1H), 8.89 (d, J =2.0 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 7.41 (s, 1H), 7.41-7.07 (m, 7H),6.97 (s, 1H), 5.94 (dd, J = 6.5, 4.3 Hz, 1H), 5.36 (d, J = 2.3 Hz, 2H),4.19 (s, 2H), 3.12-2.92 (m, 1H), 2.92-2.65 (m, 1H), 2.59- 2.32 (m, 1H),2.21-1.94 (m, 1H), 1.35-1.16 (m, 2H), 1.01 (d, J = 2.7 Hz, 2H). 606.2

¹H NMR (400 MHz, Methanol-d₄) δ 9.00 (d, J = 2.1 Hz, 1H), 8.90 (d, J =1.9 Hz, 1H), 8.44 (t, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.47-7.13 (m, 7H),7.03 (s, 1H), 5.98 (dd, J = 6.5, 4.3 Hz, 1H), 5.38 (d, J = 2.8 Hz, 2H),4.07 (s, 2H), 3.01 (ddd, J = 16.3, 8.3, 5.5 Hz, 1H), 2.81 (ddd, J =16.2, 8.2, 5.5 Hz, 1H), 2.51 (dddd, J = 11.6, 6.4, 5.2, 2.9 Hz, 3H),2.39-2.24 (m, 2H), 2.24- 2.02 (m, 2H), 1.99-1.85 (m, 1H). 598.2

¹H NMR (400 MHz, Methanol-d) δ 8.97 (s, 1H), 8.92 (s, 1H), 8.41 (s, 1H),7.57 (s, 1H), 7.48-7.35 (m, 5H), 7.32-7.19 (m, 3H), 6.10 (dd, J = 16 Hz,3.6 Hz, 1H), 5.49-5.29 (m, 3H), 4.44-4.28 (m, 2H), 4.12- 4.04 (m, 1H),3.65 (d, J = 6.8 Hz, 1H), 3.44-3.32 (m, 1H), 3.16-3.02 (m, 2H), 1.32 (d,J = 6.4 Hz, 3H). 620.2

¹H NMR (400 MHz, Methanol-d₄) δ 8.97 (d, J = 2.0 Hz, 1H), 8.90 (s, 1H),8.39 (s, 1H), 7.93 (s, 1H), 7.45- 7.31 (m, 6H), 7.26 (t, J = 7.4 Hz,1H), 7.24-7.17 (m, 1H), 6.03 (s, 1H), 4.21-3.93 (m, 2H), 3.83- 3.68 (m,1H), 3.68-3.56 (m, 1H), 3.09-2.96 (m, 1H), 2.90-2.76 (m, 1H), 2.63-2.47(m, 1H), 2.22- 2.12 (m, 1H), 1.29 (s, 3H). 572.1

¹H NMR (400 MHz, Methanol-d₄) δ 9.00 (s, 1H), 8.91 (s, 1H), 8.45 (s,1H), 7.47 (s, 1H), 7.28 (dd, J = 15.5, 8.2 Hz, 2H), 7.15 (dd, J = 7.2,1.4 Hz, 1H), 7.05 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80-6.66 (m, 1H),6.05-5.88 (m, 1H), 5.37 (s, 2H), 4.90-4.55 (m, 2H), 4.37 (d, J = 4.9 Hz,2H), 4.33-4.30 (m, 2H), 4.23-4.12 (m, 1H), 4.02-3.91 (m, 1H), 3.04-2.66(m, 2H), 2.59- 2.48 (m, 1H), 2.13-2.06 (m, 1H), 1.30-1.25 (m, 3H). 676.1

¹H NMR (400 MHz, Methanol-d₄) δ 9.06-8.94 (m, 1H), 8.93 (d, J = 2.0 Hz,1H), 8.44 (td, J = 2.1, 0.7 Hz, 1H), 7.55 (d, J = 0.7 Hz, 1H), 7.46-7.11(m, 7H), 7.05 (s, 1H), 6.00 (dd, J = 6.4, 4.4 Hz, 1H), 5.37 (d, J = 3.2Hz, 2H), 4.17 (s, 2H), 3.10-2.90 (m, 1H), 2.82 (ddd, J = 16.2, 8.2, 5.6Hz, 1H), 2.66-2.41 (m, 1H), 2.36-1.96 (m, 3H), 1.96- 1.55 (m, 6H). 612.1

TABLE 1B MS: (ES) RP HPLC Compound Structure m/z (M + H) R_(t) (min)

573.1 2.48

578.1 2.49

573.1 2.2

588 1.71

600.0. 1.58

518.4 2.32

584 1.72

603.9. 1.82

600.3 2.23

566.4 2.68

600.3. 3.54*

570.3 3.42*

636.5 2.13

581.3. 2.28

627.5 1.29

613.5 1.57

612.5. 2.4

612.5 2.31

620.4 2.25

484.4. 1.91

494.4 2

618.5 2.05

632.3. 2.95

614.2 3.65*

627.4 3.45*

628.4. 3.55*

614.4 3.82*

554.5 2.16

614.4. 3.89*

496.3 4.3*

664.4 2.73

602.4. 2.2

672.4 2.44

614.4 2.35

630.4. 2.33

602.4 2.65

536.5 2.19

598.4. 3.79*

570.5 2.27

586.5 2.16

637.3.

614.5 2.36

601.4 3.46*

644.4. 2.75

616.4 3.17

657.4 2.55

642.5. 2.37

614.5 2.01

616.4 4.05*

549.3 3.75

614.5 2.35

586.4. 2.87

620.4 2.73

583.4 3.84*

640.5 2.07

659.4 3.57*

583.2 3.81*

594.4 3.92*

602.2 3.86*

602.4 1.76

559.4 3.17*

596.3 2.19

558.3 2.47

557.4 2.4

600.4 2.25

529.4 1.81

572.4 2.09

590.4 3.57*

664.4 2.52

584.5 2.26

602.4 2.46

572.3 2.42

602.2 3.56*

620.1 2.27

573.2 2.08

506.2 2.62

522 2.48

514.1 2.39

616.2 2.45

668.1 2.5

557.2 1.98

600.2 2.37

644.2 3.97*

571.2 2.08

587.2 2.28

603.2 2.28

516.2 2.36

536.2 2.78

638.2 2.67

634.2 2.57

TABLE 1C MS: (ES) RP HPLC Compound Structure m/z (M + H) R_(t) (min)

656.1 2.51

672 2.72

688 2.81

679 2.49

658 2.38

646.1 3.49*

584.1 2.42

584.1 2.99

678.2 1.9

598.2 3.18

594.2 2.57

648.2 2.05

597 2.53

635 1.93

646.2 2.45

655 2.49

572 3.46*

607.2 2.01

665 2.23

688.2 4.18*

598.2 3.12

642.1 2.55

660.1 2.21

674.1 4.41*

684.1 2.767

600.1 2.51

598.2 2.61

586.2 2.43

598.2

598.2 2.5

643.2 2.49

702.2 2.2

645.1 2.22

702.1 4.11*

688.2 2.63

659.2 2.13

762.2 2.23

659.2 2.17

645.1 2.22

675.1 2.39

619.2 2.67

660 2.26

646.2 2.38

601.2 2.7

752.2 2.48

662.2 2.31

629.2 2.62

580.1 2.11

643.2 2.53

[M + Na]733.2 2.34

615.1 2.45

667 2.68

597 (M − 19) 2.72

[M + Na] 633.1 2.49

608.2 2.85

585.1 2.52

598.2 2.52

589 2.4

572.1 2.27

598.2 2.6

584.2 2.29

646.2 2.14

641.3 2.2

594.1 2.46

664.2 2.34

641.2 2.04

642.2 2.28

586.1 2.02

613.2 1.99

656.2 2.62

608.2 2.77

629.2. 1.94

592.2. 2.46

631.2. 2.57

679.2. 2.04

643.2 3.35

659.2. 1.86

670.3. 1.59

650.2. 1.59

594.1. 1.8

646.2. 2.13

649.2. 2.52

659.2. 2.12

659.2. 2.12

629.1. 2.16

607.2. 2.52

657.2. 1.64

600.1. 2.54

641.0. 2.42

645.1. 2.36

664.2. 2.34

638.2. 2.02

615.1. 2.37

616.1. 2.23

643.2. 2.35

650.1 2.66

631.2. 2.13

638.1. 2.41

632.1 2.26

586.0. 1.99

560.1. 2.53

628.2 2.37

556.2 2.53

614.2 3.6

616.1. 2.26

596.1 2.64

586.1. 1.8

602.1. 2.27

588.1. 2.41

600.1 2.03

614.1 2.35

600.1 1.91

660.1 3.62*

620.1 2.79

620.1 2.68

600.0. 1.74

544.2 3.62

574.2 3.57

604.1 3.48

598.2. 2.45

598.2. 2.32

394.1 4.49*

626.2 2.38

658.2 2.58

644.2 2.78

650.1 2.4

634.1 2.64

Reverse phase HPLC conditions used for determination of retention timesin Table 1B and Table 1C:

-   -   Column: ZORBAX (SB-C18 2.1×50 mm, 5 m)    -   Mobile phase A: 95% H₂O, 5% MeCN (with 0.1% Formic Acid)    -   Mobile phase B: 5% H₂O, 95% MeCN (with 0.1% Formic Acid)    -   Flow rate: 1.0 mL/min    -   Gradient: 20 to 100% B in 3.5 min (for R_(t) without *) or 20 to        100% B in 5.5 min (for R_(t) with *)

Example 48: Enzyme-Linked Immunosorbent Assay—ELISA

Plates were coated with 1 μg/mL of human PD-L1 (obtained from R&D) inPBS overnight at 4° C. The wells were then blocked with PBS containing2% BSA in PBS (W/V) with 0.05% TWEEN-20 for 1 hour at 37° C. The plateswere washed 3 times with PBS/0.05% TWEEN-20 and the samples were dilutedto 1:5 in dilution medium in the ELISA plates. Human PD-1 and biotin 0.3μg/mL (ACRO Biosystems) were added and incubated for 1 hour at 37° C.then washed 3 times with PBS/0.05% TWEEN-20. A second block was addedwith PBS containing 2% BSA in PBS (W/V)/0.05% TWEEN-20 for 10 min at 37°C. and was washed 3 times with PBS/0.05% TWEEN-20. Streptavidin-HRP wasadded for 1 hour at 37° C. then washed 3 times with PBS/0.05% TWEEN-20.TMB substrate was added and reacted for 20 min at 37° C. A stop solution(2N aqueous H₂SO₄) was added. The absorbance was read at 450 nm using amicro-plate spectrophotometer. The results are shown in Tables 2 and 3.

Compounds in Table 2 and Table 3 were prepared by methods as describedin the Examples, and evaluated according to the assay below. The IC₅₀ ofthe compounds are presented in Table 2 and Table 3 as follows:

+, 20000 nM≥IC₅₀≥500 nM;++, 500 nM>IC₅₀≥100 nM;+++, 100 nM>IC₅₀.

TABLE 2 ELISA IC₅₀ Compound Number Compound Structure (nM) 1.001

+++ 1.002

++ 1.003

+++ 1.004

+++ 1.005

+++ 1.006

++ 1.007

++ 1.008

+++ 1.009

+++ 1.010

++ 1.011

+ 1.012

+ 1.013

+ 1.014

++ 1.015

+ 2.001

++ 2.002

+++ 2.003

+++ 2.004

+++ 2.005

+++ 2.006

+++ 2.007

++ 2.008

++ 2.009

+ 2.010

+++ 2.011

+ 2.012

+ 2.103

++ 2.014

++ 2.015

+++ 2.016

+ 2.017

+ 2.018

++ 2.019

+++ 2.020

++ 2.021

+ 2.022

+++ 2.023

++ 2.024

+++ 2.025

++ 2.026

+ 2.027

+ 2.028

+++ 2.029

+++ 2.030

++ 2.031

+++ 2.032

+++ 2.033

+ 2.034

++ 2.035

++ 2.036

+++ 2.037

+++ 2.038

++ 2.039

+++ 2.040

+++ 2.041

+ 2.042

+ 2.043

+++ 2.044

++ 2.045

+++ 2.046

+++ 2.047

+++ 2.048

+++ 2.049

+ 2.050

+++ 2.051

+++ 2.052

++ 2.053

++ 2.054

+ 2.055

++ 2.056

+++ 2.057

+++ 2.058

+++ 2.059

+ 2.060

++ 2.061

+ 2.062

+ 2.063

+++ 2.064

+++ 2.065

+++ 2.066

+ 2.067

+++ 2.068

++ 2.069

+ 2.070

+++ 2.071

++ 2.072

++ 2.073

+++ 2.074

++ 2.075

++ 2.076

++ 2.077

++ 2.078

+ 2.079

++ 2.080

++ 2.081

++ 2.082

+ 2.083

++ 2.084

+++ 2.085

+ 2.086

+ 2.087

+ 2.088

+ 2.089

+ 2.090

++ 2.091

++ 2.092

++ 2.093

+ 2.094

++ 2.095

+ 2.096

+ 2.097

+ 2.098

+++ 2.099

+++ 2.100

+++ 2.101

+++ 2.102

+++ 2.103

+++ 2.104

+ 2.105

++ 2.106

+++ 2.107

+++ 2.108

+ 2.109

+ 2.110

+ 2.111

++ 2.112

+ 2.113

+ 2.114

+ 2.115

+++ 2.116

+ 2.117

+++ 2.118

+++ 2.119

++ 2.120

+ 2.121

++ 2.122

+++ 2.123

++ 2.124

+ 2.125

+++ 2.126

++ 2.127

+++ 2.128

+++ 2.129

+++ 2.130

++ 2.131

++ 2.132

++ 2.133

++ 2.134

+++ 2.135

++ 2.136

++ 2.137

++ 2.138

+++ 2.139

+++ 2.140

+++ 2.141

+++ 2.142

++ 2.143

++ 2.144

+++ 2.145

+++ 2.146

+++ 2.147

+++ 2.148

+ 2.149

++ 2.150

++ 2.151

+ 2.152

+++ 2.153

++ 2.154

++ 2.155

++ 2.156

++ 2.157

++ 2.158

++ 2.159

+++ 2.160

+++ 2.161

+++ 2.162

+ 2.163

++ 2.164

+++ 2.165

+++ 2.166

++ 2.167

++ 2.168

++ 2.169

+ 2.170

+ 2.171

++ 2.172

+ 2.173

+ 2.174

+ 2.175

++ 2.176

+++ 2.177

++ 2.178

++

TABLE 3 Structures and Activity Compound ELISA Number Compound StructureIC₅₀ (nM) 3.001

+++ 3.002

+++ 3.003

+++ 3.004

+++ 3.005

+++ 3.006

+++ 3.007

+++ 3.008

+++ 3.009

+++ 3.010

+++ 3.011

+++ 3.012

+ 3.013

+ 3.014

+ 3.015

+++ 3.016

+++ 3.017

+++ 3.018

+++ 3.019

+++ 3.020

+++ 3.021

+++ 3.022

+++ 3.023

++ 3.024

+++ 3.025

+++ 3.026

+++ 3.027

+++ 3.028

+ 3.029

++ 3.030

++ 3.031

++ 3.032

+++ 3.033

+++ 3.034

+++ 3.035

++ 3.036

++ 3.037

+++ 3.038

+++ 3.039

+++ 3.040

+++ 3.041

+++ 3.042

+ 3.043

+++ 3.044

+++ 3.045

+ 3.046

+ 3.047

+++ 3.048

+++ 3.049

+++ 3.050

++ 3.051

++ 3.052

++ 3.053

+++ 3.054

+++ 3.055

++ 3.056

+ 3.057

+++ 3.058

++ 3.059

+++ 3.060

+++ 3.061

++ 3.062

+++ 3.063

+++ 3.064

+ 3.065

+ 3.066

++ 3.067

+ 3.068

+++ 3.069

+++ 3.070

+++ 3.071

+++ 3.072

+++ 3.073

+ 3.074

+++ 3.075

++ 3.076

++ 3.077

++ 3.078

+ 3.079

++ 3.080

+++ 3.081

+ 3.082

++ 3.083

+++ 3.084

+++ 3.085

+ 3.086

+++ 3.087

+ 3.088

++ 3.089

++ 3.090

++ 3.091

+++ 3.092

++ 3.093

++ 3.094

+++ 3.095

+++ 3.096

++ 3.097

+ 3.098

++ 3.099

++ 3.100

+++ 3.101

++ 3.102

+ 3.103

++ 3.104

+++ 3.105

++ 3.106

++ 3.107

+ 3.108

++ 3.109

+ 3.110

+++ 3.111

+ 3.112

++ 3.113

+ 3.114

+ 3.115

+ 3.116

+ 3.117

+++ 3.118

+++ 3.119

+++ 3.120

+++ 3.121

+ 3.122

+++ 3.123

+ 3.124

++ 3.125

+ 3.126

++ 3.127

+++ 3.128

+++ 3.129

+++ 3.130

+++ 3.131

+++ 3.132

+++ 3.133

++ 3.134

+++ 3.135

+ 3.136

+

1.-3. (canceled)
 4. The method of claim 41, or a pharmaceuticallyacceptable salt thereof comprising administering to the subject atherapeutically effective amount of a compound of formula (IIa)


5. The method of claim 41, or a pharmaceutically acceptable salt thereofcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (IIb)

6.-8. (canceled)
 9. The method of claim 41, or a pharmaceuticallyacceptable salt thereof wherein R¹ is phenyl, wherein the phenyl isoptionally substituted with 1 to 5 R^(x) substituents.
 10. The method ofclaim 41 or a pharmaceutically acceptable salt thereof, wherein R¹ isphenyl optionally substituted with 1 or 2 R^(x) wherein each R^(x) isindependently selected from halogen, C₁₋₈ alkyl, O—C₁₋₈ alkyl, O—C₁₋₈haloalkyl, —NR^(a)R^(b), and CN.
 11. The method of claim 41 or apharmaceutically acceptable salt thereof, wherein R¹ is phenyloptionally substituted with F.
 12. The method of claim 41 or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromthe group consisting of:


13. (canceled)
 14. The method of claim 41 or a pharmaceuticallyacceptable salt thereof, wherein R^(2b) and R^(2c) are both H and R^(2a)is selected from the group consisting of halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₁₋₃ haloalkyl, —CN, —OMe and OEt.
 15. The method of claim 41or a pharmaceutically acceptable salt thereof, wherein R^(2b) and R^(2c)are both H and R^(2a) is halogen.
 16. The method of claim 41 or apharmaceutically acceptable salt thereof, wherein R^(2b) and R^(2c) areboth H and R^(2a) is Cl.
 17. The method of claim 41 or apharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 andeach R⁵ is independently selected from the group consisting of halogen,—CN, —R^(q), —NR^(r)R^(s), and —OR^(r), wherein each R^(r) and R^(s) isindependently selected from hydrogen, C₁₋₈alkyl and C₁₋₈ haloalkyl andeach R^(q) is independently selected from the group consisting of C₁₋₈alkyl and C₁₋₈ haloalkyl.
 18. The method of claim 41, or apharmaceutically acceptable salt thereof, wherein n is
 0. 19. The methodof claim 41, or a pharmaceutically acceptable salt thereof, whereinR^(6a) is H.
 20. The method of claim 41, or a pharmaceuticallyacceptable salt thereof, wherein m is
 0. 21. The method of claim 41, ora pharmaceutically acceptable salt thereof, wherein m is 1 and R^(6b) isselected from the group consisting of F, C₁₋₄ alkyl, O—R^(u), C₁₋₄haloalkyl and NR^(u)R^(v), wherein each R^(u) and R^(v) is independentlyselected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl.
 22. The method ofclaim 41, or a pharmaceutically acceptable salt thereof, wherein m is 1and R^(6b) is F.
 23. The method of claim 41, or a pharmaceuticallyacceptable salt thereof, wherein


24. (canceled)
 25. The method of claim 41 or a pharmaceuticallyacceptable salt thereof wherein R⁴ is selected from the group consistingof pyridinyl, —O—C₁₋₂ alkyl-pyridinyl, wherein the pyridinyl, isoptionally substituted with 1 to 2 R^(z), wherein each R^(z) isindependently selected from the group consisting of halogen, —CN,—CO₂R^(n), —NR^(n)R^(p), —OR^(n), and piperidinyl optionally substitutedwith OH.
 26. The method of claim 41, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is selected from the group consisting of:


27. The method of claim 41, or a pharmaceutically acceptable saltthereof, wherein R⁴ is


28. The method of claim 41, or a pharmaceutically acceptable saltthereof, wherein R³ is NR^(g)R^(h), wherein R^(g) is selected from thegroup consisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl, and wherein R^(h)is —C₁₋₈ alkyl substituted with from 1 to 3 substituents independentlyselected from OH, COOH, SO₂NH₂, CONH₂, CONOH, COO—C₁₋₈ alkyl, and PO₃H₂.29. (canceled)
 30. The method of claim 41, or a pharmaceuticallyacceptable salt thereof, wherein R³ is NHR^(h), wherein R^(h) is —C₁₋₈alkyl substituted with from 1 to 2 substituents independently selectedfrom OH, COOH, CONH₂, PO₃H₂.
 31. The method of claim 41, or apharmaceutically acceptable salt thereof wherein R³ is selected from thegroup consisting of:

32.-37. (canceled)
 38. A method of modulating an immune responsemediated by the PD-1 signaling pathway in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula II

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of halogen, C₅₋₈ cycloalkyl, C₆₋₁₀ aryl,wherein the C₆₋₁₀ aryl is optionally substituted with 1 to 5 R^(x)substituents; each R^(x) is independently selected from the groupconsisting of halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b),—C(O)R^(a), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(a),—NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),—O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X—NR^(a)R^(b),—X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), whereineach X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is independentlyselected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(c) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl and C₁₋₈ haloalkyl each R^(2a), R^(2b) and R^(2c)is independently selected from the group consisting of H, halogen, —CN,—R^(d), —CO₂R^(e), —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f),—NR^(f)C(O)R^(e), —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f),—NR^(e)R^(f), —OR^(e), —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),—O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),—X²—CONR^(e)R^(f), —SF₅, —S(O)₂NR^(e)R^(f), and C₆₋₁₀ aryl, wherein eachX² is a C₁₋₄ alkylene; each R^(e) and R^(f) is independently selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(d) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl; R³ is —NR^(g)R^(h); R^(g) is selected fromthe group consisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl; R^(h) isselected from —C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH, C₁₋₈alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂, C₁₋₈alkyl-CONOH, C₁₋₈ alkyl-NR^(h1)R^(h2), —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₁₀carbocyclyl, —C₁₋₈ alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-COOH, and—C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OH optionally substituted with CO₂H;wherein R^(h1) and R^(h2) are each independently selected from the groupconsisting of H, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl; the C₁₋₈ alkylportions of R^(h) are optionally further substituted with from 1 to 3substituents independently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH,COO—C₁₋₈ alkyl, PO₃H₂ optionally substituted with 1 to 2 C₁₋₃ alkylsubstituents, the C₁₀ carbocyclyl, and the C₆₋₁₀ aryl portions of R^(h)are optionally substituted with 1 to 3 substituents independentlyselected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂,COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkylCONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, C₁₋₄alkyl-COOH, and phenyl andthe C₃₋₁₀ cycloalkyl portions of R^(h) are optionally substituted with 1to 4 R^(w) substituents; each R^(w) substituent is independentlyselected from C₁₋₄ alkyl, C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂, C₁₋₄ alkyl-CONOH, C₁₋₄ alkyl-PO₃H, OH,COO—C₁₋₈ alkyl, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂ and oxo; R⁴ isselected from the group consisting of pyridinyl and —O—C₁₋₄alkyl-pyridinyl wherein the pyridinyl is optionally substituted with 1to 5 R^(z); each R^(z) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),—O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),—X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅,—S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), wherein each X³ is a C₁₋₄ alkylene;each R^(n) and R^(p) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl; each R^(m) is independently selected from thegroup consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; n is 0,1, 2 or 3; each R⁵ is independently selected from the group consistingof halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),—OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),—NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),—O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),—X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅,—S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r) andR^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl; each R^(q) is independently selected from the groupconsisting of C₁₋₈ alkyl, and C₁₋₈ haloalkyl; R^(6a) is selected fromthe group consisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl; each R^(6b) isindependently selected from the group consisting of F, C₁₋₄ alkyl,O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each R^(u) and R^(v) isindependently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl;and m is 0, 1, 2, 3 or
 4. 39. A method of enhancing, stimulating,modulating and/or increasing the immune response in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula II

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of halogen, C₅₋₈ cycloalkyl, C₆₋₁₀ aryl,wherein the C₆₋₁₀ aryl is optionally substituted with 1 to 5 R^(x)substituents; each R^(x) is independently selected from the groupconsisting of halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b),—C(O)R^(a), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(a),—NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),—O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X—NR^(a)R^(b),—X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), whereineach X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is independentlyselected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(c) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl and C₁₋₈ haloalkyl each R^(2a), R^(2b) and R^(2c)is independently selected from the group consisting of H, halogen, —CN,—R^(d), —CO₂R^(e), —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f),—NR^(f)C(O)R^(e), —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f),—NR^(e)R^(f), —OR^(e), —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),—O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),—X²—CONR^(e)R^(f), —SF₅, —S(O)₂NR^(e)R^(f), and C₆₋₁₀ aryl, wherein eachX² is a C₁₋₄ alkylene; each R^(e) and R^(f) is independently selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(d) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl; R³ is —NR^(g)R^(h); R^(g) is selected fromthe group consisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl; R^(h) isselected from —C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH, C₁₋₈alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂, C₁₋₈alkyl-CONOH, C₁₋₈ alkyl-NR^(h1)R^(h2), —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₁₀carbocyclyl, —C₁₋₈ alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-COOH, and—C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OH optionally substituted with CO₂H;wherein R^(h1) and R^(h2) are each independently selected from the groupconsisting of H, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl; the C₁₋₈ alkylportions of R^(h) are optionally further substituted with from 1 to 3substituents independently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH,COO—C₁₋₈ alkyl, PO₃H₂ optionally substituted with 1 to 2 C₁₋₃ alkylsubstituents, the C₁₀ carbocyclyl, and the C₆₋₁₀ aryl portions of R^(h)are optionally substituted with 1 to 3 substituents independentlyselected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂,COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkylCONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, C₁₋₄alkyl-COOH, and phenyl andthe C₃₋₁₀ cycloalkyl portions of R^(h) are optionally substituted with 1to 4 R^(w) substituents; each R^(w) substituent is independentlyselected from C₁₋₄ alkyl, C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂, C₁₋₄ alkyl-CONOH, C₁₋₄ alkyl-PO₃H, OH,COO—C₁₋₈ alkyl, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂ and oxo; R⁴ isselected from the group consisting of pyridinyl and —O—C₁₋₄alkyl-pyridinyl wherein the pyridinyl is optionally substituted with 1to 5 R^(z); each R^(z) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),—O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),—X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅,—S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), wherein each X³ is a C₁₋₄ alkylene;each R^(n) and R^(p) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl; each R^(m) is independently selected from thegroup consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; n is 0,1, 2 or 3; each R⁵ is independently selected from the group consistingof halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),—OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),—NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),—O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),—X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅,—S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r) andR^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl; each R^(q) is independently selected from the groupconsisting of C₁₋₈ alkyl, and C₁₋₈ haloalkyl; R^(6a) is selected fromthe group consisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl; each R^(6b) isindependently selected from the group consisting of F, C₁₋₄ alkyl,O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each R^(u) and R^(v) isindependently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl;and m is 0, 1, 2, 3 or
 4. 40. A method of inhibiting growth,proliferation, or metastasis of cancer cells in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula II,

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of halogen, C₅₋₈ cycloalkyl, C₆₋₁₀ aryl,wherein the C₆₋₁₀ aryl is optionally substituted with 1 to 5 R^(x)substituents; each R^(x) is independently selected from the groupconsisting of halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b),—C(O)R^(a), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(a),—NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),—O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X—NR^(a)R^(b),—X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), whereineach X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is independentlyselected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(c) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl and C₁₋₈ haloalkyl each R^(2a), R^(2b) and R^(2c)is independently selected from the group consisting of H, halogen, —CN,—R^(d), —CO₂R^(e), —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f),—NR^(f)C(O)R^(e), —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f),—NR^(e)R^(f), —OR^(e), —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),—O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),—X²—CONR^(e)R^(f), —SF₅, —S(O)₂NR^(e)R^(f), and C₆₋₁₀ aryl, wherein eachX² is a C₁₋₄ alkylene; each R^(e) and R^(f) is independently selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(d) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl; R³ is —NR^(g)R^(h); R^(g) is selected fromthe group consisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl; R^(h) isselected from —C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH, C₁₋₈alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂, C₁₋₈alkyl-CONOH, C₁₋₈ alkyl-NR^(h1)R^(h2), —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₁₀carbocyclyl, —C₁₋₈ alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-COOH, and—C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OH optionally substituted with CO₂H;wherein R^(h1) and R^(h2) are each independently selected from the groupconsisting of H, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl; the C₁₋₈ alkylportions of R^(h) are optionally further substituted with from 1 to 3substituents independently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH,COO—C₁₋₈ alkyl, PO₃H₂ optionally substituted with 1 to 2 C₁₋₃ alkylsubstituents, the C₁₀ carbocyclyl, and the C₆₋₁₀ aryl portions of R^(h)are optionally substituted with 1 to 3 substituents independentlyselected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂,COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkylCONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, C₁₋₄alkyl-COOH, and phenyl andthe C₃₋₁₀ cycloalkyl portions of R^(h) are optionally substituted with 1to 4 R^(w) substituents; each R^(w) substituent is independentlyselected from C₁₋₄ alkyl, C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂, C₁₋₄ alkyl-CONOH, C₁₋₄ alkyl-PO₃H, OH,COO—C₁₋₈ alkyl, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂ and oxo; R⁴ isselected from the group consisting of pyridinyl and —O—C₁₋₄alkyl-pyridinyl wherein the pyridinyl is optionally substituted with 1to 5 R^(z); each R^(z) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),—O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),—X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅,—S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), wherein each X³ is a C₁₋₄ alkylene;each R^(n) and R^(p) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl; each R^(m) is independently selected from thegroup consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; n is 0,1, 2 or 3; each R⁵ is independently selected from the group consistingof halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),—OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),—NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),—O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),—X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅,—S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r) andR^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl; each R^(q) is independently selected from the groupconsisting of C₁₋₈ alkyl, and C₁₋₈ haloalkyl; R^(6a) is selected fromthe group consisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl; each R^(6b) isindependently selected from the group consisting of F, C₁₋₄ alkyl,O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each R^(u) and R^(v) isindependently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl;and m is 0, 1, 2, 3 or
 4. 41. A method of treating a subject sufferingfrom or susceptible to a disease or disorder mediated by the PD-1signaling pathway, comprising administering to the subject atherapeutically effective amount of a compound of Formula II,

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of halogen, C₅₋₈ cycloalkyl, C₆₋₁₀ aryl,wherein the C₆₋₁₀ aryl is optionally substituted with 1 to 5 R^(x)substituents; each R^(x) is independently selected from the groupconsisting of halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b),—C(O)R^(a), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(a),—NR^(a)—C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a),—O—X¹—CO₂R^(a), —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X—NR^(a)R^(b),—X¹—CO₂R^(a), —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), whereineach X¹ is a C₁₋₄ alkylene; each R^(a) and R^(b) is independentlyselected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(c) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl and C₁₋₈ haloalkyl each R^(2a), R^(2b) and R^(2c)is independently selected from the group consisting of H, halogen, —CN,—R^(d), —CO₂R^(e), —CONR^(e)R^(f), —C(O)R^(e), —OC(O)NR^(e)R^(f),—NR^(f)C(O)R^(e), —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f),—NR^(e)R^(f), —OR^(e), —O—X²—OR^(e), —O—X²—NR^(e)R^(f), —O—X²—CO₂R^(e),—O—X²—CONR^(e)R^(f), —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e),—X²—CONR^(e)R^(f), —SF₅, —S(O)₂NR^(e)R^(f), and C₆₋₁₀ aryl, wherein eachX² is a C₁₋₄ alkylene; each R^(e) and R^(f) is independently selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; each R^(d) isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and C₁₋₈ haloalkyl; R³ is —NR^(g)R^(h); R^(g) is selected fromthe group consisting of H, C₁₋₈ haloalkyl and C₁₋₈ alkyl; R^(h) isselected from —C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH, C₁₋₈alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂, C₁₋₈alkyl-CONOH, C₁₋₈ alkyl-NR^(h1)R^(h2), —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₁₀carbocyclyl, —C₁₋₈ alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈alkyl-NH(C═O)—C₁₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-COOH, and—C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OH optionally substituted with CO₂H;wherein R^(h1) and R^(h2) are each independently selected from the groupconsisting of H, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl; the C₁₋₈ alkylportions of R^(h) are optionally further substituted with from 1 to 3substituents independently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH,COO—C₁₋₈ alkyl, PO₃H₂ optionally substituted with 1 to 2 C₁₋₃ alkylsubstituents, the C₁₀ carbocyclyl, and the C₆₋₁₀ aryl portions of R^(h)are optionally substituted with 1 to 3 substituents independentlyselected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂,COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkylCONH₂, C₁₋₄alkyl-CONOH, C₁₋₄alkyl-PO₃H₂, C₁₋₄alkyl-COOH, and phenyl andthe C₃₋₁₀ cycloalkyl portions of R^(h) are optionally substituted with 1to 4 R^(w) substituents; each R^(w) substituent is independentlyselected from C₁₋₄ alkyl, C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂, C₁₋₄ alkyl-CONOH, C₁₋₄ alkyl-PO₃H, OH,COO—C₁₋₈ alkyl, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂ and oxo; R⁴ isselected from the group consisting of pyridinyl and —O—C₁₋₄alkyl-pyridinyl wherein the pyridinyl is optionally substituted with 1to 5 R^(z); each R^(z) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X³—OR^(n),—O—X³—NR^(n)R^(p), —O—X³—CO₂R^(n), —O—X³—CONR^(n)R^(p), —X³—OR^(n),—X³—NR^(n)R^(p), —X³—CO₂R^(n), —X³—CONR^(n)R^(p), —SF₅,—S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), wherein each X³ is a C₁₋₄ alkylene;each R^(n) and R^(p) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl; each R^(m) is independently selected from thegroup consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; n is 0,1, 2 or 3; each R⁵ is independently selected from the group consistingof halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),—OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),—NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁴—OR^(r),—O—X⁴—NR^(r)R^(s), —O—X⁴—CO₂R^(r), —O—X⁴—CONR^(r)R^(s), —X⁴—OR^(r),—X⁴—NR^(r)R^(s), —X⁴—CO₂R^(r), —X⁴—CONR^(r)R^(s), —SF₅,—S(O)₂NR^(r)R^(s), wherein each X⁴ is a C₁₋₄ alkylene; each R^(r) andR^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl; each R^(q) is independently selected from the groupconsisting of C₁₋₈ alkyl, and C₁₋₈ haloalkyl; R^(6a) is selected fromthe group consisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl; each R^(6b) isindependently selected from the group consisting of F, C₁₋₄ alkyl,O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each R^(u) and R^(v) isindependently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl;and m is 0, 1, 2, 3 or
 4. 42.-45. (canceled)
 46. The method of claim 41,wherein the compound of Formula II is selected from the group consistingof


47. The method of claim 41, wherein the compound of Formula II isselected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 48. The method of claim41, wherein the compound of Formula II has the formula:

or a pharmaceutically acceptable salt thereof.
 49. The method of claim41, wherein the compound of Formula II has the formula:

or a pharmaceutically acceptable salt thereof.
 50. The method of claim41, wherein the compound of Formula II has the formula:

or a pharmaceutically acceptable salt thereof.
 51. The method of claim41, wherein the compound of Formula II has the formula:

or a pharmaceutically acceptable salt thereof.